Process for producing optically active naphthalene derivative and optical resolver therefor

ABSTRACT

The present invention provides a method of producing an optically active form of a compound represented by the formula (I) having a steroid C 17,20 -lyase inhibitory activity and is useful as an agent for the prophylaxis or treatment of prostatism, tumor such as breast cancer, and the like or a salt thereof, which method includes reacting a mixture of optically active compounds of a naphthalene derivative represented by the formula:                    
     wherein R is a nitrogen-containing heterocyclic group, R 1  is a hydrogen atom, a hydrocarbon group or an aromatic heteromonocyclic group, R 2  is a hydrogen atom or a lower alkyl group, * shows the position of an asymmetric carbon, R 3 , R 4 , R 5 , R 6 , R 7 , R 8  and R 9  are each independently a hydrogen atom, a hydrocarbon group, a hydroxy group, a thiol group, an amino group, a carbamoyl group, an acyl group or a halogen atom, and R 7  is bonded with R 6  or R 8  to form, together with a carbon atom on a naphthalene ring, a 5 or 6-membered ring containing an oxygen atom, with an optically active form of a compound represented by the formula:                    
     wherein ring A is a benzene ring, R 10  and R 11  are the same or different and each is a hydrogen atom, a hydrocarbon group or a halogen atom, or R 10  and R 11  in combination show an alkylene group, * shows the position of an asymmetric carbon, and ring B and ring C are each an aromatic ring, separating the resulting salt, and isolating the optically active form, and a novel reagent for optical resolution.

This application is the National Phase filing of International PatentApplication No. PCT/JP00/07282, filed Oct. 19, 2000.

TECHNICAL FIELD

The present invention relates to a production method of an opticallyactive naphthalene derivative having a pharmacological action,particularly a steroid C_(17,20)-lyase inhibitory activity, a reagentfor optical resolution thereof and a production method of the reagentfor optical resolution. More specifically, the present invention relatesto a production method of naphthalene derivatives which comprises use ofan optically active cyclic phosphorus compound as a reagent for opticalresolution, a salt formed during the optical resolution, a noveloptically active dioxaphosphorinan useful as a reagent for opticalresolution, a reagent for optical resolution containing a noveloptically active dioxaphosphorinan and a production method of thereagent for optical resolution.

BACKGROUND ART

Since chemically synthesized naphthalene derivatives represented by theformula (I) have an asymmetric carbon and have two kinds of opticalisomers, there is a demand for a technique to selectively andefficiently prepare an optically active form thereof. For the productionof an optically active amino compound, it is a general practice to usewhat is called a diastereomer salt method which comprises reacting anoptically active acid compound with an amino compound (racemate) andseparating the resulting salt mixture based on differences in thephysical properties. For use of this method, various optically activeacidic compounds have been developed and utilized as reagents foroptical resolution (Separation Purification Technique Handbook, TheChemical Society of Japan, Maruzen, p. 459 (1993)).

Some of the optically active compounds represented by the formula (II)can be prepared according to the method described in JP-A-61-103886 andthe like and are used for the optical resolution of amino acids, such asp-hydroxyphenyl glycine and phenylalanine, and amino compounds, such as1-phenyl-2-paramethoxyphenyl-ethylamine and1,2-di(4′-chlorophenyl)-1,2-diamino-ethane.

An optically active compound represented by the formula (III) can beproduced according to the method described in JP-B-55-47013 and the likeand is used as a reagent for the resolution of amino acids such asadrenaline, lysine, glutamic acid and the like, amphetamines, basicantibiotics such as lincomycin, tetracycline and the like, atropine,scopolamine, catecholamine, ephedrine, morphine, phenothiazines,perhexilin, prostaglandins and intermediates therefor,α-p-ethoxyphenylamino-N-n-propyl-propionamide,α,α-diphenyl-α-(2-piperidine)methanol, DOPA and many other amines.

Of the reagents for optical resolution of amino compounds, an opticallyactive dioxaphosphorinan described in The Journal of Organic Chemistry,Vol. 50, p. 4508 (1985) and JP-A-61-103886 shows relatively highefficiency of optical resolution and can be derived easily. Therefore,it characteristically permits selection of a preferable one from variousreagents for optical resolution.

As a production method of an optically active dioxaphosphorinan, amethod comprising optical resolution of a racemate of dioxaphosphorinanis disclosed in the above-mentioned publications.

On the other hand, what is called an asymmetric synthetic method,wherein an optically active compound is directly produced withoutrelying on optical resolution, is remarkably progressing in recentyears. For synthesis of an optically active hydroxyester compound, forexample, asymmetric hydrogenation using aruthenium—2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (abbreviated asBINAP) complex (Journal of the American Chemical Society, Vol. 109, p.5856 (1987), asymmetric hydrogenation using1,2-bis(tert-butylmethylphosphino)ethane (abbreviated as BisP*)(Tetrahedron Letters, Vol. 40, p. 2577 (1999)), and asymmetrichydrogenation using 1,2-bis(trans-2,5-diisopropylphosphorano)ethane(abbreviated as i-Pr-BPE) (Journal of the American Chemical Society,Vol. 117, p. 4423 (1995)) are known.

While an optically active dioxaphosphorinan shows a relatively highresolution efficiency and versatility as a reagent for opticalresolution, it is frequently found to be unsuitable for opticalresolution of an intermediate for a pharmaceutical product having acomplicated chemical structure.

According to a method disclosed for the synthesis of optically activedioxaphosphorinan, dioxaphosphorinan as a racemate is optically resolvedby a diastereomer salt method. Therefore, its theoretical yield does notexceed 50%. Moreover, this method requires an optically active amine inan equivalent amount as a reagent for optical resolution, but theoptically active amine is not necessarily easily available. Thus, thismethod is not economically advantageous.

DISCLOSURE OF THE INVENTION

The present invention provides a method for producing (R) or (S)-(I)having a high optical purity by efficient optical resolution of amixture of optical isomers of a naphthalene derivative represented bythe formula (I), a general-purpose reagent for optical resolution, whichis superior in resolution efficiency, and a method for producing theresolution reagent in a high yield and in an industrially advantageousmanner.

The present inventors have found that the above-mentioned objects can beachieved by converting optical isomers of a naphthalene derivativerepresented by the formula (I) in a mixture to diastereomer salts withan optically active acidic compound and separating the salts, andintensively investigated further to complete the present invention.

Accordingly, the present invention relates to

(1) a production method of an optically active form of a compoundrepresented by the formula:

 wherein R is a nitrogen-containing heterocyclic group optionally havingsubstituents, R¹ is a hydrogen atom, a hydrocarbon group optionallyhaving substituents, or a aromatic heteromonocyclic group optionallyhaving substituents, R² is a hydrogen atom or a lower alkyl groupoptionally having substituents, * shows the position of an asymmetriccarbon, R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ are each independently a hydrogenatom, a hydrocarbon group optionally having substituents, a hydroxygroup optionally having substituents, a thiol group optionally havingsubstituents, an amino group optionally having substituents, an acylgroup or a halogen atom, and R⁷ may be bonded with R⁶ or R⁸ to form,together with a carbon atom on a naphthalene ring, a 5 or 6-memberedring containing an oxygen atom, or a salt thereof, which comprisesreacting a mixture of optically active compounds of the naphthalenederivative represented by the formula (I) with an optically active formof a compound represented by the formula:

 wherein ring A is a benzene ring optionally having substituents, R¹⁰and R¹¹ are the same or different and each is a hydrogen atom, ahydrocarbon group optionally having substituents or a halogen atom, orR¹⁰ and R¹¹ in combination represent an alkylene group optionally havingsubstituents, and * shows the position of an asymmetric carbon, or anoptically active form of a compound represented by the formula:

 wherein ring B and ring C are each an aromatic ring optionally havingsubstituents, separating the resulting salt and isolating an opticallyactive form,

(2) the production method according to the above-mentioned (1), whereinthe nitrogen-containing heterocyclic group optionally havingsubstituents, which is represented by R, is an imidazolyl groupoptionally having substituents, a thiazolyl group optionally havingsubstituents, an oxazolyl group optionally having substituents or apyridyl group optionally having substituents,

(3) the production method according to the above-mentioned (1), whereinthe nitrogen-containing heterocyclic group optionally havingsubstituents, which is represented by R, is a 4 or 5-imidazolyl groupoptionally having substituents or a 3 or 4-pyridyl group optionallyhaving substituents,

(4) the production method according to the above-mentioned (1), wherein,when the nitrogen-containing heterocyclic group optionally havingsubstituents, which is represented by R, is an oxazolyl group optionallyhaving substituents or a thiazolyl group optionally having substituents,R¹ is a saturated hydrocarbon group optionally having substituents, whenR is a pyridyl group and either R¹ or R² is a hydrogen atom, R⁷ is ahydroxy group optionally having substituents or a lower alkyl groupoptionally having substituents, and when R is an oxazolyl optionallyhaving substituents and R¹ is a hydrogen atom, R² is a lower alkyl groupoptionally having substituents,

(5) the production method according to the above-mentioned (1) or (4),wherein R¹ is a hydrogen atom, a lower alkyl group optionally havingsubstituents, a lower alkenyl group optionally having substituents, acyclic alkyl group optionally having substituents or a phenyl groupoptionally having substituents,

(6) the production method according to the above-mentioned (1) or (4),wherein R¹ is a lower alkyl group,

(7) the production method according to the above-mentioned (1) or (4),wherein R² is a hydrogen atom or a lower alkyl group,

(8) the production method according to the above-mentioned (1) or (4),wherein R¹ is a C₁₋₆ alkyl group and R² is a hydrogen atom,

(9) the production method according to the above-mentioned (1) or (4),wherein R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ are each independently a hydrogenatom, a hydrocarbon group optionally having substituents, a hydroxygroup optionally having substituents, an amino group optionally havingsubstituents or an acyl group,

(10) the production method according to the above-mentioned (1) or (4),wherein 1 to 3 of R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ are each independently ahydrogen atom, a hydrocarbon group optionally having substituents, ahydroxy group optionally having substituents or an acyl group,

(11) the production method according to the above-mentioned (1) or (4),wherein R⁷ is [1] a hydroxy group optionally having, as a substituent, alower alkanoyl group, a lower alkanoyloxy(lower)alkyl group, a loweralkyl group, a lower alkoxy(lower)alkyl group, a lower alkyl groupoptionally substituted by 1 to 4 fluorine atoms, or a benzyl group, [2]a halogen atom, [3] a lower alkyl group optionally substituted by ahydroxy group, [4] a lower alkynyl group, [5] a lower alkanoyl group,[6] amino group optionally having a lower alkanoyl group, a loweralkylaminocarbonyl group or a lower alkylsulfonyl group as asubstituent, [7] a lower alkylthio group or [8] a carbamoyl groupoptionally having substituents,

(12) the production method according to the above-mentioned (1) or (4),wherein R⁷ is a lower alkyl group, a hydroxy group optionally havingsubstituents, a lower alkanoylamino group, or a carbamoyl groupoptionally having substituents,

(13) the production method according to the above-mentioned (1) or (4),wherein R⁸ is a hydrogen atom, a lower alkyl group or a lower alkoxy,

(14) the production method according to the above-mentioned (1) or (4),wherein R⁶ is [1] a hydrogen atom, [2] a halogen atom, [3] a loweralkoxy group or [4] a lower alkyl group optionally substituted by ahydroxy group,

(15) the production method according to the above-mentioned (1) or (4),wherein either R⁶, R⁷ or R⁸ is a lower alkyl group or a lower alkoxygroup,

(16) the production method according to the above-mentioned (1) or (4),wherein R³, R⁴, R⁵ and R⁹ are a hydrogen atom,

(17) the production method according to the above-mentioned (1) or (4),wherein R⁷ is a methylcarbamoyl and R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ are ahydrogen atom,

(18) the production method according to the above-mentioned (1) or (4),wherein the naphthalene derivative represented by the formula (I) is1-(1H-imidazol-4-yl)-1-(6-methoxynaphthalen-2-yl)-2-methyl-1-propanol,1-(6,7-dimethoxynaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol,1-(6-methoxy-5-methylnaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol,N-{6-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]naphthalen-2-yl}acetamide,N-{6-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]-N-methyl-2-naphthamide,N-{6-[1-hydroxy-1-(1H-imidazol-4-yl)propyl]-N-methyl-2-naphthamide orN-{6-[1-hydroxy-1-(1H-imidazol-4-yl)-3-methylbutyl]-N-methyl-2-naphthamide,

(19) the production method according to the above-mentioned (1) or (4),wherein a compound represented by the formula (I) and an opticallyactive form of a compound represented by the formula (II) are reacted,

(20) the production method according to the above-mentioned (19) whereinthe compound represented by the formula (II) is a compound representedby the formula:

 wherein ring A and * mean as defined above, and Alk is a C₂₋₄ alkyleneoptionally having substituents,

(21) the production method according to the above-mentioned (20) whereinthe compound represented by the formula (IIa) is a compound representedby the formula:

 wherein * means as defined above,

(22) a salt of an optically active compound represented by the formula:

 wherein Q¹ is an optically active form of a compound represented by theformula:

 wherein R¹⁰ and R¹¹ are the same or different and each is a hydrogenatom, a hydrocarbon group optionally having substituents or a halogenatom, or R¹⁰ and R¹¹ in combination represent an alkylene groupoptionally having substituents and ring A is as defined above, or anoptically active form of a compound represented by the formula:

 wherein each symbol is as defined above,

(23) a salt of an optically active compound represented by the formula:

 wherein Q² is an optically active form of a compound represented by theformula:

 wherein ring B and ring C are each as defined above, or an opticallyactive form of a compound represented by the formula:

 wherein each symbol is as defined above, and other symbols are asdefined above,

(24) a salt represented by the formula:

 a salt represented by the formula:

 a salt represented by the formula:

 a salt represented by the formula:

 or a salt represented by the formula:

(25) a compound represented by the formula (IIa) or a salt thereof,

(26) the compound of the above-mentioned (25), which is an opticallyactive form,

(27) a production method of an optically active form of a compoundrepresented by the formula (II), or a salt thereof, which comprisessubjecting a compound represented by the formula:

 wherein R¹² is a hydrogen atom, a lower alkyl group optionally havingsubstituents or an aryl group optionally having substituents, and othersymbols are as defined above, or a salt thereof, to an asymmetrichydrogenation reaction, reducing an optically active form of theobtained compound represented by the formula;

 wherein each symbol is as defined above, or a salt thereof, andsubjecting an optically active form of the obtained compound representedby the formula:

 wherein each symbol is as defined above, or a salt thereof, tophosphorylation,

(28) the production method according to the above-mentioned (27),wherein the asymmetric hydrogenation reaction is carried out in thepresence of a ruthenium complex with an optically active compoundrepresented by the formula:

 wherein R¹³ and R¹⁴ are different and each is a hydrocarbon groupoptionally having substituents or a heterocyclic ring optionally havingsubstituents, and * means as defined above, or a salt thereof, and

(29) a reagent for optical resolution which comprises an opticallyactive form of a compound represented by the formula (IIa) or a saltthereof.

In the above-mentioned formulas, the “nitrogen-containing heterocyclicgroup” of the “nitrogen-containing heterocyclic group optionally havingsubstituents” represented by R is exemplified by a nitrogen-containingaromatic heterocyclic group or a saturated or an unsaturatednitrogen-containing non-aromatic heterocyclic group (nitrogen-containingaliphatic heterocyclic group), having, as an atom (ring atom)constituting the ring, at least one nitrogen atom, which is preferably anitrogen-containing aromatic heterocyclic group. Examples of thenitrogen-containing aromatic heterocyclic group include 5 or 6-memberednitrogen-containing aromatic heterocyclic group such as imidazolyl,pyrrolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl,thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, 1,3,5-triazinyl and 1,2,4-triazinyl. Of these,imidazolyl, pyridyl, thiazolyl, oxazolyl and the like, particularly 4 or5-imidazolyl group and 3 or 4-pyridyl group, are preferable.

The substituent of the “nitrogen-containing aromatic heterocyclic groupoptionally having substituents” represented by R may be present in thenumber of 1 to 3 at substitutable positions of the nitrogen-containingaromatic heterocyclic group. Examples of the substituent include loweralkyl group, lower alkoxy group, acyl group and the like, whichoptionally have substituents. Examples of the “lower alkyl groupoptionally having substituents” include non-substituted C₂₋₄ alkyl groupsuch as methyl, ethyl, propyl and the like, such alkyl group substitutedby C₁₋₆ alkanoyl (e.g., acetyl, propionyl etc.), carboxyl, C₁₋₄alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl,butoxycarbonyl etc.) and the like. Examples of the “lower alkoxy group”include C₁₋₃ alkoxy group such as methoxy, ethoxy, propoxy, isopropoxyand the like.

Examples of the “acyl group” include alkanoyl group (e.g., C₁₋₆ alkanoylsuch as formyl, acetyl, propionyl etc.), alkylsulfonyl group (e.g., C₁₋₄alkylsulfonyl such as methylsulfonyl, ethylsulfonyl etc.), arylsulfonylgroup (e.g., benzenesulfonyl, p-toluenesulfonyl etc.), carbamoyl groupoptionally having substituents (e.g., mono- or di-C₁₋₁₀ alkylcarbamoylgroup such as methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl,diethylcarbamoyl etc., mono- or di-C₆₋₁₄ arylcarbamoyl such asphenylcarbamoyl, diphenylcarbamoyl etc., mono- or di-C₇₋₁₆aralkylcarbamoyl group such as benzylcarbamoyl, dibenzylcarbamoyl etc.,and the like), sulfamoyl group optionally having substituents (e.g.,mono- or di-C₁₋₁₀ alkylsulfamoyl group such as methylsulfamoyl,ethylsulfamoyl, dimethylsulfamoyl, diethylsulfamoyl etc., mono- ordi-C₆₋₁₄ arylsulfamoyl group such as phenylsulfamoyl, diphenylsulfamoyletc., mono- or di-C₇₋₁₆ aralkylsulfamoyl group such as benzylsulfamoyl,dibenzylsulfamoyl etc., and the like), lower alkoxy-carbonyl group(e.g., C₁₋₄ alkoxy-carbonyl group such as ethoxycarbonyl,ethoxycarbonyl, butoxycarbonyl etc., and the like), and the like.

Examples of the “hydrocarbon group” of the “hydrocarbon group optionallyhaving substituents” represented by R¹ include chain hydrocarbon group,cyclic hydrocarbon group and the like.

Examples of the “chain hydrocarbon group” include linear or branchedhydrocarbon groups having 1 to 10 carbon atoms, and the like, which isspecifically alkyl group, alkenyl group, alkynyl group and the like. Ofthese, alkyl group is particularly preferable. Examples of the “alkylgroup” include C₁₋₁₀ alkyl groups such as methyl, ethyl, n-propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl,neopentyl, n-hexyl, isohexyl and the like, and the like, of which C₁₋₆alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl,sec-butyl, tert-butyl etc.) is preferable. Examples of the “alkenylgroup” include C₂₋₁₀ alkenyl groups such as vinyl, 1-propenyl, allyl,isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, isobutenyl, sec-butenyland the like, and the like, of which C₂₋₆ alkenyl group (e.g., vinyl,1-propenyl, allyl etc.) is preferable. Examples of the “alkynyl group”include C₂₋₁₀ alkynyl groups such as ethynyl, 1-propnyl, propargyl etc.,and the like, of which C₂₋₆ alkynyl group (e.g., ethynyl and the like)is preferable.

Examples of the “cyclic hydrocarbon group” include cyclic hydrocarbongroup having 3 to 18 carbon atoms, such as alicyclic hydrocarbon group,aromatic hydrocarbon group and, the like.

Examples of the “alicyclic hydrocarbon group” include monocyclic orfused polycyclic group consisting of 3 to 10 carbon atom, which isspecifically cycloalkyl group, cycloalkenyl group and 2 or 3 cyclicfused ring of these and C₆₋₁₄ aryl group (e.g., benzene etc.) and thelike, and the like. Examples of the “cycloalkyl group” include C₃₋₆cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl etc., and the like, examples of the “cycloalkenyl group”include C₃₋₆ cycloalkenyl group such as cyclopropenyl, cyclobutenyl,cyclopentenyl, cyclohexenyl etc., and the like.

Examples of the “aromatic hydrocarbon group” include monocyclic aromatichydrocarbon group consisting of 6 to 18 carbon atoms, fused polycyclicaromatic hydrocarbon group and the like, which is specifically C₆₋₁₄aryl group such as phenyl, 1-naphthyl, 2-naphthyl, 2-indenyl, 2-anthryland the like and C₆₋₁₀ aryl group (e.g., phenyl etc.) and the like arepreferable.

The substituent that the “chain hydrocarbon group” in the “hydrocarbongroup optionally having substituents” may have is not particularlylimited and examples thereof include halogen atom, hydroxy group, alkoxygroup, acyloxy group, alkylthio group, acylamino group, carboxyl group,alkoxycarbonyl group, oxo group, alkanoyl group, cycloalkyl group, arylgroup, aromatic heterocyclic group and the like. These substituents issubstituted in the range chemically acceptable on the “chain hydrocarbongroup” wherein the number of the substituent is 1 to 5, preferably 1 to3. When the number of the substituents is 2 or above, they may be thesame or different.

Examples of the “halogen atom” include fluorine, chlorine, bromine,iodine and the like.

Examples of the “alkoxy group” include C₁₋₁₀ alkoxy group such asmethoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy,pentyloxy, hexyloxy etc., and the like. Examples of the “acyloxy group”include formyloxy, C₁₋₁₀ alkylcarbonyloxy group (e.g., acetoxy,propionyloxy etc.) and the like. Examples of the “alkylthio group”include C₁₋₁₀ alkylthio group such as methylthio, ethylthio, propylthio,isopropylthio etc., and the like. Examples of the “acylamino group”include formylamino, diformylamino, mono- or di-C₁₋₁₀ alkylcarbonylaminogroup (e.g., acetylamino, propionylamino, butyrylamino, diacetylaminoetc.) and the like. Examples of the “alkoxycarbonyl group” include C₁₋₁₀alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl etc., and the like.Examples of the “alkanoyl group” include C₁₋₁₀ alkylcarbonyl group suchas acetyl, propionyl, butyryl, valeryl etc., and the like. Examples ofthe “cycloalkyl group” include C₃₋₁₀ cycloalkyl group such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc., and the like.Examples of the “aryl group” include C₆₋₁₄ aryl group such as phenyl,1-naphthyl, 2-naphthyl etc. , and the like. Examples of the “aromaticheterocyclic group” include 1 to 3 cyclic aromatic heterocyclic groupscontaining, besides carbon atom, preferably 1 to 4 of 1 or 2 kinds ofheteroatom selected from nitrogen, oxygen and sulfur, and the like.Specific examples thereof include thienyl, pyridyl, furyl, pyrazinyl,pyrimidinyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl,isoxazolyl, pyridazinyl, tetrazolyl, quinolyl, indolyl, isoindolyl andthe like.

The substituent that the “cyclic hydrocarbon group” in the “hydrocarbongroup optionally having substituents” may possess is not particularlylimited. Examples thereof include halogen atom, hydroxy group, alkoxygroup, acyloxy group, alkylthio group, alkylsulfonyl group, mono- ordi-alkylamino group, acylamino group, carboxyl group, alkoxycarbonylgroup, alkanoyl group, alkynylcarbonyl group, alkyl group, cycloalkylgroup, aryl group, aromatic heterocyclic group and the like. Thesesubstituents are substituted on the “cyclic hydrocarbon group” in achemically acceptable range, wherein the number of the substituent is 1to 5, preferably 1 to 3. When the number of substituents is 2 or above,they may be the same or different. Of these substituents, halogen atom,alkoxy group, acyloxy group, alkylthio group, acylamino group,alkoxycarbonyl group, alkanoyl group, cycloalkyl group, aryl group andaromatic heterocyclic group are similar to those defined above as thesubstituent on the “chain hydrocarbon group”.

Examples of the “alkylsulfonyl group” include C₁₋₁₀ alkylsulfonyl groupssuch as methylsulfonyl, ethylsulfonyl, propylsulfonyl etc., and thelike. Examples of the “alkylamino group” include mono-C₁₋₄ alkylaminogroups such as methylamino, ethylamino, propylamino and the like,di-C₁₋₄ alkylamino groups such as dimethylamino, diethylamino and thelike, examples of the “alkynylcarbonyl group” include C₃₋₁₀alkynylcarbonyl groups such as ethynylcarbonyl, 1-propynylcarbonyl,2-propynylcarbonyl etc., and the like. Example of the “alkyl group”include C₁₋₁₀ alkyl groups such as methyl, ethyl, propyl, isopropyl,butyl, sec-butyl, tert-butyl, pentyl etc., and the like.

The substituent that the aforementioned “hydrocarbon group” may have, ina chemically acceptable range, 1 to 5, preferably 1 to 3, substituentsshown below. Examples of such substituent include halogen atom (e.g.,fluorine, chlorine, bromine etc.), hydroxy group, C₁₋₆ alkoxy group(e.g., methoxy, ethoxy, propoxy, isopropoxy etc.), and the like.

Examples of the aromatic heteromonocyclic group of the “aromaticheteromonocyclic group optionally having substituents” represented by R¹include 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl,3-furyl, pyrazinyl, 2-pyrimidinyl, 3-pyrrolyl, 1-imidazolyl,2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 1-pyrazolyl, 2-thiazolyl,4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 2-oxazolyl,4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 3-pyridazinyl and the like. Ofthese, 2-pyridyl, 3-pyridyl, 4-pyridyl, 1-imidazolyl, 4-imidazolyl andthe like are preferable.

The substituent of the “aromatic heteromonocyclic group optionallyhaving substituents” represented by R¹ may be substituted in the numberof 1 to 3 at substitutable positions of the aromatic heteromonocyclicgroup. Examples of the substituent include alkyl group optionallysubstituted by 1 to 5 halogen atoms (e.g., fluorine, chlorine, bromine,iodine), which is exemplified by C₁₋₄ alkyl group such as methyl, ethyl,propyl etc. and C₁₋₄ alkyl group substituted by halogen such as2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl etc., C₁₋₃ alkoxygroup such as methoxy, ethoxy, propoxy, isopropoxy etc., halogen atomsuch as chlorine atom, fluorine atom etc., hydroxy group, amino group,nitro group and the like.

Of the aforementioned examples, preferable as R¹ are hydrogen atom,lower alkyl group (those having 1 to 4 carbon atoms) optionally havingsubstituents, lower alkenyl group (those having 1 to 4 carbon atoms),cyclic alkyl group (those having 3 to 6 carbon atoms), phenyl groupoptionally having substituents and pyridyl group optionally havingsubstituents. Of these, hydrogen atom, lower alkenyl group (those having1 to 4 carbon atoms), cyclic alkyl group (those having 3 to 6 carbonatoms), phenyl group, pyridyl group and lower alkyl group (those having1 to 4 carbon atoms) optionally having halogen as substituent areparticularly preferable.

Examples of the lower alkyl group of R² include chain or cyclic C₁₋₆alkyl group optionally having substituents (e.g., methyl, ethyl, propyl,isopropyl, cyclopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,cyclopentyl, hexyl etc.). The C₁₋₆ alkyl group may have 1 to 5substituents at substitutable positions and examples of the substituentinclude halogen (e.g., fluorine, chlorine, bromine, iodine), C₁₋₄ alkoxygroup (e.g., methoxy, ethoxy, propoxy etc.) and the like.

Preferable examples of R² are, of the aforementioned, hydrogen atom andnon-substituted lower alkyl group (those having 1 to 6 carbon atoms),particularly preferably hydrogen atom.

Examples of the “hydroxy group optionally having substituents”represented by R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ include, besidesnon-substituted hydroxy group, lower alkoxy group (e.g., C₁₋₄ alkoxygroup such as methoxy, ethoxy, propoxy etc.), lower alkanoyloxy group(e.g., C₁₋₄ alkanoyloxy such as acetyloxy, propionyloxy etc.),carbamoyloxy group optionally having substituents (e.g., non-substitutedcarbamoyloxy and carbamoyloxy substituted by 1 or 2 C₁₋₄ alkyl groupssuch as, ethylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy,diethylcarbamoyloxy, methylethylcarbamoyloxy etc.), and the like.

Examples of the “thiol group optionally having substituents” representedby R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ include, besides non-substituted thiolgroup, lower alkylthio group (e.g., C₁₋₄ alkylthio group such asmethylthio, ethylthio, propylthio etc.), lower alkanoylthio group (e.g.,C₁₋₄ alkanoylthio such as acetylthio, propionylthio etc.), and the like.

Examples of the “amino group optionally having substituents” representedby R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ include, besides non-substituted aminogroup, lower alkylamino group (e.g., C₁₋₄ alkylamino group such asmethylamino, ethylamino, propylamino etc.), di-lower alkylamino group(e.g., di-C₁₋₄ alkylamino such as dimethylamino, diethylamino etc.),C₁₋₄ alkanoylamino group (e.g., acetamide, propionamide etc.), and thelike.

Examples of the acyl group represented by R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹include alkanoyl group (e.g., C₁₋₆ alkanoyl such as formyl, acetyl,propionyl etc.), arylsulfonyl group (e.g., benzenesulfonyl,p-toluenesulfonyl etc.), carbamoyl group optionally having substituents(besides non-substituted carbamoyl group, mono- or di-C₁₋₄alkylcarbamoyl group such as methylcarbamoyl, ethylcarbamoyl,dimethylcarbamoyl, diethylcarbamoyl group etc., mono- or di-C₆₋₁₄arylcarbamoyl group such as phenylcarbamoyl, diphenylcarbamoyl groupetc., mono- or di-C₇₋₁₆ aralkylcarbamoyl group such as benzylcarbamoyl,dibenzylcarbamoyl etc.), alkylsulfonyl group (e.g., C₁₋₄ alkylsulfonylsuch as methylsulfonyl, ethylsulfonyl etc.), sulfamoyl group optionallyhaving substituents (e.g., mono- or di-C₁₋₁₀ alkylsulfamoyl group suchas methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, diethylsulfamoyletc., mono- or di-C₆₋₁₄ arylsulfamoyl group such as phenylsulfamoyl,diphenylsulfamoyl etc., mono- or di-C₇₋₁₆ aralkylsulfamoyl group such asbenzylsulfamoyl, dibenzylsulfamoyl etc., and the like), loweralkoxy-carbonyl group (e.g., C₁₋₄ alkoxy-carbonyl group such asmethoxycarbonyl, ethoxycarbonyl, butoxycarbonyl etc., and the like), andthe like.

Examples of the halogen represented by R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹include fluorine, chlorine, bromine and iodine.

Examples of the “hydrocarbon group optionally having substituents”represented by R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ include those similar tothe “hydrocarbon group optionally having substituents” represented byR¹. Of these, lower alkyl group optionally having substituents ispreferable. Examples thereof include chain or cyclic C₁₋₆ alkyl groupoptionally having substituents (e.g., methyl, ethyl, propyl, isopropyl,cyclopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,cyclopentyl, hexyl etc.). The C₁₋₆ alkyl group may have 1 to 5substituents at substitutable positions, and examples of the substituentinclude halogen (e.g., fluorine, chlorine, bromine, iodine), C₁₋₄ alkoxygroup (e.g., methoxy, ethoxy, propoxy etc.), hydroxy group, and thelike. The C₁₋₄ alkoxy group may have 1 to 5 substituents atsubstitutable positions, and examples of the substituent include halogen(e.g., fluorine, chlorine, bromine, iodine), C₁₋₄ alkoxy group (e.g.,methoxy, ethoxy, propoxy etc.), and the like.

Preferable examples of the R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ include, of theaforementioned examples, hydrogen atom, hydrocarbon group optionallyhaving substituents, hydroxy group optionally having substituents, aminogroup optionally having substituents, carbamoyl group optionally havingsubstituents, C₁₋₆ alkanoyl group and halogen atom.

Of R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ R⁷ is preferably an optionallysubstituted hydroxy group or a lower alkyl group. It is preferably (1)hydroxy group optionally having, as a substituent, lower alkanoyl group,lower alkanoyloxy(lower)alkyl group, lower alkyl group, loweralkoxy(lower)alkyl group, lower alkyl group optionally substituted by 1to 4 fluorine atoms or benzyl group, (2) halogen atom, (3) lower alkylgroup optionally substituted by hydroxy group, (4) lower alkynyl group,(5) lower alkanoyl group, (6) amino group optionally having loweralkanoyl group, lower alkylaminocarbonyl group and lower alkylsulfonylgroup as a substituent or (7) lower alkylthio group, more preferablylower alkyl group, lower alkoxy group, lower alkanoylamino group orlower alkylcarbamoyl group. R⁸ is preferably hydrogen atom, lower alkylgroup or lower alkoxy group, more preferably hydrogen atom or loweralkoxy group. R⁶ is preferably (1) hydrogen atom, (2) halogen atom, (3)lower alkoxy group or (4) lower alkyl group optionally substituted byhydroxy group, more preferably hydrogen atom or lower alkyl group.

Examples of the combination of R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ is thatwherein 1 to 3 thereof are each preferably independently lower alkylgroup optionally having substituents, hydroxy group optionally havingsubstituents, amino group optionally having substituents, carbamoylgroup optionally having substituents, C₁₋₆ alkanoyl group or halogenatom.

It is preferable that any of R⁶, R⁷ and R⁸ is lower alkyl group, loweralkoxy group, lower alkanoylamino group or lower alkylcarbamoyl group,and that all of R³, R⁴, R⁵ and R⁹ are hydrogen atoms.

Of the compounds (I), a compound wherein R¹ is C₁₋₆ alkyl group and R²is hydrogen atom.

When R⁷ is bonded with R⁶ or R⁸ and form, together with carbon atom onthe naphthalene ring, a 5 or 6-membered ring containing oxygen atom,examples of the ring include furan ring, dihydrofuran ring, pyran ring,dihydropyran ring, dioxolen ring, oxazole ring, isoxazole ring and thelike.

Preferable examples of the compound represented by the formula (I)include compounds of the formulas

wherein each symbol is as defined above, and the like. Examples of thepreferable compound include1-(1H-imidazol-4-yl-1-(6-methoxynaphthalen-2-yl)-2-methyl-1-propanol,1-(6,7-dimethoxynaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol,1-(6-methoxy-5-methylnaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol,N-{6-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]naphthalen-2-yl}acetamideandN-{6-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]-N-methyl-2-naphthamide.

In the aforementioned formulas, ring A may have 1 to 5, preferably 1 or2 substituents at optional positions. Examples of the substituentinclude lower alkyl group optionally having substituents, hydroxy groupoptionally having substituents, thiol group optionally havingsubstituents, nitro group, amino group optionally having substituents,acyl group, halogen atom, methylenedioxy group optionally havingsubstituents (or adjacent two substituents are bonded) and the like.

Examples of the lower alkyl group of the “optionally substituted loweralkyl group” include C₁₋₆ alkyl group such as methyl, ethyl, propyl,isopropyl, butyl, pentyl, hexyl and the like. Examples of thesubstituent include halogen atom such as fluorine, chlorine, bromine andthe like, C₁₋₇ alkoxy group such as methoxy, ethoxy, propoxy, benzyloxyand the like, C₁₋₇ alkylthio group such as methylthio, ethylthio,propiothio, benzylthio and the like, hydroxy group, and substitutedamino group such as acetylamino, benzoylamino, methanesulfonylamino,benzenesulfonylamino and the like.

Examples of the hydroxy group optionally having substituents include,besides non-substituted hydroxy group, lower alkoxy group (e.g., linearor branched C₁₋₆ alkoxy group such as methyloxy, ethyloxy, n-propyloxy,isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy,pentyloxy, hexyloxy etc.), lower alkanoyloxy group (e.g., C₁₋₄alkanoyloxy such as acetyloxy, propionyloxy etc.), carbamoyloxy groupoptionally having substituents (e.g., non-substituted carbamoyloxy,carbamoyloxy substituted by 1 or 2 C₁₋₄ alkyl groups such asmethylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy,diethylcarbamoyloxy, methylethylcarbamoyloxy etc.) and the like.

Examples of the thiol group optionally having substituents include,besides non-substituted thiol group, lower alkylthio group (e.g., C₁₋₄alkylthio group such as methylthio, ethylthio, propylthio etc.), loweralkanoylthio group (e.g., C₁₋₄ alkanoylthio such as acetylthio,propionylthio etc.) and the like.

Examples of the amino group optionally having substituents include,besides non-substituted amino group, lower alkylamino group (e.g., C₁₋₄alkylamino group such as methylamino, ethylamino, propylamino etc.),di-lower alkylamino group (e.g., di-C₁₋₄ alkylamino such asdimethylamino, diethylamino etc.), C₁₋₄ alkanoylamino group (e.g.,acetamide, propionamide etc.) and the like.

Examples of the acyl group include alkanoyl group (e.g., C₁₋₆ alkanoylsuch as formyl, acetyl, propionyl etc.), alkylsulfonyl group (e.g., C₁₋₄alkylsulfonyl such as methylsulfonyl, ethylsulfonyl etc.), arylsulfonylgroup (e.g., benzenesulfonyl, p-toluenesulfonyl etc.), carbamoyl groupoptionally having substituents (e.g., mono- or di-C₁₋₁₀ alkylcarbamoylgroup such as methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl,diethylcarbamoyl etc., mono- or di-C₆₋₁₄ arylcarbamoyl such asphenylcarbamoyl, diphenylcarbamoyl etc., mono- or di-C₇₋₁₆aralkylcarbamoyl group such as benzylcarbamoyl, dibenzylcarbamoyl etc.,and the like), sulfamoyl group optionally having substituents (e.g.,mono- or di-C₁₋₁₀ alkylsulfamoyl group such as methylsulfamoyl,ethylsulfamoyl, dimethylsulfamoyl, diethylsulfamoyl etc., mono- ordi-C₆₋₁₄ arylsulfamoyl group such as phenylsulfamoyl, diphenylsulfamoyletc., mono- or di-C₇₋₁₆ aralkylsulfamoyl group such as benzylsulfamoyl,dibenzylsulfamoyl etc., and the like), lower alkoxy-carbonyl group(e.g., C₁₋₄ alkoxy-carbonyl group such as methoxycarbonyl,ethoxycarbonyl, butoxycarbonyl etc., and the like) and the like.

Examples of the halogen atom include fluorine, chlorine, bromine andiodine.

The methylenedioxy group optionally having substituents are substitutedat the two adjacent carbons of the benzene ring, and examples thereofinclude, besides non-substituted methylenedioxy group, and saidmethylene group substituted by, for example, halogen (e.g., fluorineatom, chlorine atom, bromine atom, iodine), nitro group, hydroxy group,amino group and the like.

When ring A has a substituent, preferable examples thereof includehalogen atom, alkyl group and alkoxy group. Particularly preferableexamples of the ring A include non-substituted one and one havingchlorine atom and/or methoxy group as substituent. The positions ofsubstitution are 2-position, 4-position, and 2-, 4-positions.

As a preferable example of R¹⁰ and R¹¹, a case where both and R¹² aremethyl groups and a case where R¹⁰ and R¹¹ are bonded to showtetramethylene group are mentioned. Examples of the hydrocarbon groupoptionally having substituents, which is represented by R¹⁰ and R¹¹,include, besides non-substituted C₁₋₄ alkyl group such as methyl, ethyl,propyl and the like, these having substituents such as C₂₋₅ alkanoylsuch as acetyl, propionyl etc., carboxyl, C₁₋₄ alkoxy-carbonyl group(e.g., methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl etc.) and thelike, at optional positions and the like.

Examples of the halogen atom represented by R¹⁰ and R¹¹ include fluorineatom, chlorine atom, bromine atom, iodine atom and the like.

When R¹⁰ and R¹¹ in combination show an alkylene group optionally havingsubstituents, examples of the “alkylene group optionally havingsubstituents” include non-substituted alkylene having 2 to 5 carbonatoms (dimethylene, trimethylene, tetramethylene, pentamethylene), thesealkylene having, at optional positions, substituents such as lower alkylgroup (e.g., C₁₋₄ alkyl such as methyl, ethyl, propyl etc.), loweralkoxy group (e.g., C₁₋₄ alkoxy such as methoxy, ethoxy, propoxy etc.),hydroxy group, amino group, nitro group, halogen atom (e.g., fluorine,chlorine, bromine, iodine) and the like.

Examples of the lower alkyl group optionally having substituents, whichis represented by R¹², include, besides linear or branchednon-substituted C₁₋₆ alkyl group such as methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.,such alkyl group substituted by C₁₋₆ alkanoyl (e.g., acetyl, propionyletc.), carboxyl, C₁₋₄ alkoxy-carbonyl (e.g., methoxycarbonyl,ethoxycarbonyl, butoxycarbonyl etc.), and the like, and the like.

Examples of the aryl group optionally having substituents, which isrepresented by R¹², include, besides aryl group having 6 to 10 carbonatoms such as non-substituted phenyl group, naphthyl group etc., sucharyl group having substituents such as lower alkyl group (e.g., C₁₋₄alkyl such as methyl, ethyl, propyl etc.), lower alkoxy group (e.g.,C₁₋₄ alkoxy such as methoxy, ethoxy, propoxy etc.), hydroxy group, aminogroup, nitro group, halogen atom (e.g., fluorine atom, chlorine atom,bromine atom, iodine) and the like at optional positions.

As R¹², methyl and ethyl are particularly preferable.

As the C₂₋₄ alkylene optionally having substituents, which isrepresented by Alk, alkylene group optionally having substituents, whichis formed by R¹⁰ and R¹¹ in combination, wherein the alkylene moiety has2 to 4 carbon atoms, is mentioned.

Ring B and ring C are each an aromatic ring optionally havingsubstituents, which has 1 to 5, preferably 1 or 2, substituents atoptional positions. Examples of the aromatic ring include benzene ring,naphthalene ring and the like and examples of the substituent includelower alkyl group, lower alkenyl group, lower alkoxy group, loweralkylthio group, halogen atom, cyano group and the like. Examples of the“lower alkyl group” include C₁₋₆ alkyl group such as methyl, ethyl,propyl, isopropyl, butyl, pentyl and hexyl group, examples of the “loweralkenyl group” include C₂₋₆ alkenyl group such as vinyl, 1-propenyl,allyl, isopropenyl, butenyl etc., examples of the “lower alkoxy group”include C₁₋₆ alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy,butoxy and the like. Examples of the “lower alkylthio group” includeC₁₋₇ alkylthio group such as methylthio, ethylthio, propiothio,benzylthio etc. and examples of the halogen atom include chlorine,bromine and the like. Preferable examples of the ring B and ring Cinclude, besides non-substituted naphthalene ring, naphthalene ringhaving methyl group and/or methoxy group as substituents.

Examples of the hydrocarbon group of the “hydrocarbon group optionallyhaving substituents”, which is represented by R¹³ and R¹⁴, includealiphatic chain hydrocarbon group, alicyclic hydrocarbon group and thelike.

Examples of the aliphatic chain hydrocarbon group include linear orbranched aliphatic hydrocarbon such as alkyl group, alkenyl group,alkynyl group and the like. Examples of the alkyl group include C₁₋₁₀alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl,tert-pentyl etc., and the like. It is preferably lower C₁₋₆ alkyl group.Examples of the alkenyl group include C₂₋₆ alkenyl groups such as vinyl,allyl, isopropenyl, 2-methylallyl, 1-propenyl, 2-propenyl,2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl,2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 1-hexenyl etc., andthe like. Examples of the alkynyl group include C₂₋₆ alkynyl groups suchas ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, 3-butynyl, 1-pentynyl,2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl,4-hexynyl, 5-hexynyl etc., and the like.

Examples of the alicyclic hydrocarbon group include saturated orunsaturated alicyclic hydrocarbon groups such as cycloalkyl group,cycloalkenyl group, cycloalkanedienyl group and the like. Examples ofthe cycloalkyl group include C₃₋₉ cycloalkyl groups such as cyclopropyl,cyclobutyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, 1-adamantylgroup etc., and the like. Examples of the cycloalkenyl group includeC₃₋₆ cycloalkenyl groups such as 1-cyclopenten-1-yl, 2-cyclopenten-1-yl,3-cyclopenten-1-yl, 2-cyclohexan-1-yl, 3-cyclohexan-1-yl,1-cyclobuten-1-yl etc., and the like. Examples of the cycloalkadienylgroup include C₄₋₆ cycloalkadienyl groups such as2,4-cyclopentadien-1-yl, 2,4-cyclohexadien-1-yl, 2,5-cyclohexadien-1-yletc., and the like.

Examples of the heterocyclic group of the “heterocyclic s groupoptionally having substituents”, which is represented by R¹³ and R¹⁴,include aromatic heterocyclic group, saturated or unsaturatednon-aromatic heterocyclic group (aliphatic heterocyclic group) and thelike, which contain, as an atom constituting the ring (ring atom), atleast 1 (preferably 1 to 4, more preferably 1 or 2) of 1 to 3 kinds(preferably 1 or 2 kinds) of heteroatoms selected from oxygen atom,sulfur atom, nitrogen atom and the like.

Examples of the “aromatic heterocyclic group” include 5 or 6-memberedaromatic heteromonocyclic group such as aromatic heteromonocyclic group(e.g., furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl,1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl,pyrazinyl, triazinyl etc.) and the like and 8 to 12-membered aromaticfused heterocyclic group such as aromatic fused heterocyclic group(e.g., benzofuranyl, isobenzofuranyl, benzothienyl, indolyl, isoindolyl,1H-indazolyl, benzindazolyl, benzoxazolyl, 1,2-benzoisoxazolyl,benzothiazolyl, 1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl,isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl,naphthyridinyl, purinyl, pteridinyl, carbazolyl, α-carbolinyl,β-carbolinyl, a-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl,phenazinyl, phenoxathiinyl, thianthrenyl, phenanthridinyl,phenanthrolinyl, indolizinyl, pyrrolo[1,2-b]pyridazinyl,pyrazolo[1,5-a]pyridyl, imidazo[1,2-b]pyridyl, imidazo[1,5-b]pyridyl,imidazo[1,2-a]pyridazinyl, imidazo[1,2-a]pyrimidinyl,1,2,4-triazolo[4,3-a]pyridyl, 1,2,4-triazolo[4,3-b]pyridazinyl etc.) andthe like, with preference given to heterocyclic ring obtained bycondensation of the aforementioned 5 to 6-membered aromaticheteromonocyclic group with benzene ring or heterocyclic ring obtainedby condensation of the same or different two heterocyclic rings of theaforementioned 5 or 6-membered aromatic heteromonocyclic group) and thelike.

Examples of the “non-aromatic heterocyclic group” include 3 to8-membered (preferably 5 or 6-membered) saturated or unsaturated(preferably saturated) non-aromatic heterocyclic group (aliphaticheterocyclic group) such as oxiranyl, azetidinyl, oxetanyl, thietanyl,pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl,morpholinyl, thiomorpholinyl, piperazinyl etc. and the like. As thesubstituent that the “heterocyclic group optionally having substituents”as a substituent may have, lower alkyl group (e.g., C₁₋₆ alkyl groupsuch as methyl, ethyl, propyl etc., and the like), acyl group (e.g.,C₁₋₆ alkanoyl such as formyl, acetyl, propionyl, pivaloyl etc., benzoyland the like), and the like are mentioned.

Examples of the substituent of the “hydrocarbon group optionally havingsubstituents” and “heterocyclic group optionally having substituents”,which are represented by R¹³ or R¹⁴, include aryl group optionallyhaving substituents, cycloalkyl group optionally having substituents,cycloalkenyl group optionally having substituents, alkyl groupoptionally having substituents, alkenyl group optionally havingsubstituents, alkynyl group optionally having substituents, heterocyclicgroup optionally having substituents, amino group optionally havingsubstituents, imidoyl group optionally having substituents, amidinogroup optionally having substituents, hydroxy group optionally havingsubstituents, thiol group optionally having substituents, optionallyesterified or amidated carboxyl group, thiocarbamoyl group optionallyhaving substituents, halogen atom (e.g., fluorine, chlorine, bromine,iodine), cyano group, nitro group, acyl group derived from sulfonicacid, acyl group derived from carboxylic acid and the like, wherein thenumber of these optional substituents present at substitutable positionsis 1 to 5, preferably 1 to 3.

Examples of the aryl group of the “aryl group optionally havingsubstituents” as a substituent include C₆₋₁₄ aryl group such as phenyl,naphthyl, anthryl, phenanthryl, acenaphthylenyl etc., and the like.Examples of the substituent of the aryl group here include lower alkoxygroup (e.g., C₁₋₆ alkoxy group such as methoxy, ethoxy, propoxy etc.,and the like), halogen atom (e.g., fluorine, chlorine, bromine, iodine),lower alkyl group (e.g., C₁₋₆ alkyl group such as methyl, ethyl, propyletc., and the like), amino group, hydroxy group, cyano group, amidinogroup and the like, wherein the number of these optional substituentspresent at substitutable positions is 1 or 2.

Examples of the cycloalkyl group of the “cycloalkyl group optionallyhaving substituents” as a substituent include C₃₋₇ cycloalkyl group suchas cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc.,and the like. Examples of the substituent of the cycloalkyl group hereinclude those similar in number and kind to the substituents of theaforementioned “aryl group optionally having substituents”.

Examples of the cycloalkenyl group of the “cycloalkenyl group optionallyhaving substituents” as a substituent include C₃₋₆ cycloalkenyl groupsuch as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl etc.,and the like. Examples of the substituent of the cycloalkenyl groupoptionally having substituents here include those similar in number andkind to the substituents of the aforementioned “aryl group optionallyhaving substituents”.

Examples of the alkyl group of the “alkyl group optionally havingsubstituents” as a substituent include C₁₋₆ alkyl such as methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,isopentyl, neopentyl, 1-methylpropyl, n-hexyl, isohexyl,1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl,3,3-dimethylpropyl etc., and the like. Examples of the substituent ofthe alkyl group include those similar in number and kind to thesubstituents of the aforementioned “aryl group optionally havingsubstituents”.

Examples of the alkenyl group of the “alkenyl group optionally havingsubstituents” as a substituent include C₂₋₆ alkenyl group such as vinyl,allyl, isopropenyl, 2-methylallyl, 1-propenyl, 2-methyl-1-propenyl,1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl, 2-methyl-2-butenyl,3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl,4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl,5-hexenyl etc., and the like. Examples of the substituent of the alkenylgroup here include those similar in number and kind to the substituentsof the aforementioned “aryl group optionally having substituents”.

Examples of the alkynyl group of the “alkynyl group optionally havingsubstituents” as a substituent include C₂₋₆ alkynyl groups such asethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl,1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl,3-hexynyl, 4-hexynyl, 5-hexynyl and the like. Examples of thesubstituents of the alkynyl group here include those similar in numberand kind to the substituents of the aforementioned “aryl groupoptionally having substituents”.

Examples of the “heterocyclic group optionally having substituents” as asubstituent include those mentioned as the heterocyclic group of the“heterocyclic group optionally having substituents” represented by R¹³and R¹⁴, and examples of the substituent include alkyl group optionallysubstituted by 1 to 5 halogen atoms (e.g., fluorine, chlorine, bromine,iodine), which is exemplified by C₁₋₄ alkyl group such as methyl, ethyl,propyl etc., C₁₋₄ alkyl group substituted by halogen, such as2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl and the like, C₁₋₃alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy and the like,halogen atom such as chlorine atom, fluorine atom and the like, hydroxygroup, amino group, nitro group and the like, which may be present inthe number of 1 to 3 at substitutable positions of the heterocyclicgroup.

Examples of the substituent of the “amino group optionally havingsubstituents”, “imidoyl group optionally having substituents”, “amidinogroup optionally having substituents”, “hydroxy group optionally havingsubstituents” and “thiol group optionally having substituents” assubstituents include lower alkyl group (e.g., C₁₋₆ alkyl group such asmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl,hexyl etc., and the like), acyl group (C₁₋₆ alkanoyl (e.g., formyl,acetyl, propionyl, pivaloyl etc.), benzoyl etc.), optionally halogenatedC₁₋₆ alkoxy-carbonyl (e.g., trifluoromethoxycarbonyl,2,2,2-trifluoroethoxycarbonyl, trichloromethoxycarbonyl,2,2,2-trichloroethoxycarbonyl etc.) and the like. The “amino group” ofthe “amino group optionally having substituents” as a substituent may besubstituted by imidoyl group optionally having substituents (e.g., C₁₋₆alkylimidoyl, formylimidoyl, amidino etc.) and the like, or twosubstituents, in combination with nitrogen atom, may form a cyclic aminogroup. In this case, examples of the cyclic amino group include 3 to8-membered (preferably 5 or 6-membered) cyclic amino such as1-azetidinyl, 1-pyrrolidinyl, piperidino, morpholino, 1-piperazinyl and1-piperazinyl optionally having, at the 4-position, lower alkyl group(e.g., C₁₋₆ alkyl group such as methyl, ethyl, propyl, isopropyl, butyl,tert-butyl, pentyl, hexyl etc., and the like), aralkyl group (e.g.,C₇₋₁₀ aralkyl group such as benzyl, phenethyl etc., and the like), arylgroup (e.g., C₆₋₁₀ aryl group such as phenyl, 1-naphthyl, 2-naphthyletc., and the like) and the like, and the like.

Examples of the “optionally esterified carboxyl group” include, besidesfree carboxyl group, lower alkoxycarbonyl group, aryloxycarbonyl group,aralkyloxycarbonyl group and the like.

Examples of the “lower alkoxycarbonyl group” include C₁₋₆alkoxy-carbonyl group such as methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl,isopentyloxycarbonyl, neopentyloxycarbonyl etc., and the like. Of these,C₁₋₃ alkoxy-carbonyl group such as methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl etc., and the like are preferable.

Preferable examples of the “aryloxycarbonyl group” include C₇₋₁₂aryloxy-carbonyl group such as phenoxycarbonyl, 1-naphthoxycarbonyl,2-naphthoxycarbonyl etc., and the like.

Preferable examples of the “aralkyloxycarbonyl group” include C₇₋₁₀aralkyloxycarbonyl group such as benzyloxycarbonyl, phenethyloxycarbonyletc., and the like (preferably C₆₋₁₀ aryl-C₁₋₄ alkoxycarbonyl etc.).

The “aryloxycarbonyl group” and “aralkyloxycarbonyl group” may have asubstituent, and examples of the substituent include those similar innumber and kind to the substituents of aryl group and aralkyl group asan example of the substituent of the N-monosubstituted carbamoyl groupto be mentioned below.

The “lower alkoxycarbonyl group” here may have substituents, andexamples of the substituent include those similar in number and kind tothe substituents of the aforementioned “aryloxycarbonyl group” and“aralkyloxycarbonyl group”.

Examples of the substituent of the “thiocarbamoyl group optionallyhaving substituents” include those similar to the substituents of the“carbamoyl group optionally having substituents” to be mentioned below.

Examples of the “optionally amidated carboxyl group” include carbamoylgroup optionally having substituents, such as, besides non-substitutedcarbamoyl, N-monosubstituted carbamoyl group and N,N-disubstitutedcarbamoyl group.

The “N-monosubstituted carbamoyl group” means a carbamoyl group havingone substituent on a nitrogen atom. Examples of the substituent includelower alkyl group (e.g., C₁₋₆ alkyl group such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl etc., and thelike), cycloalkyl group (e.g., C₃₋₆ cycloalkyl group such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc., and the like),aryl group (e.g., C₆₋₁₀ aryl group such as phenyl, 1-naphthyl,2-naphthyl etc., and the like), aralkyl group (e.g., C₇₋₁₀ aralkyl groupsuch as benzyl, phenethyl etc., preferably phenyl-C₁₋₄ alkyl group andthe like), heterocyclic group (e.g., those similar to the aforementioned“heterocyclic group” as the substituent of the “hydrocarbon groupoptionally having substituents”, which is represented by R¹³, and thelike) and the like. The lower alkyl group, cycloalkyl group, aryl group,aralkyl group and heterocyclic group may have a substituent, andexamples of the substituent include hydroxy group, amino groupoptionally having substituents [said amino group optionally has, as asubstituent, 1 or 2 from, for example, lower alkyl group (e.g., C₁₋₆alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,tert-butyl, pentyl, hexyl etc., and the like), acyl group (e.g., C₁₋₆alkanoyl such as formyl, acetyl, propionyl, pivaloyl etc., benzoyl andthe like) and the like], halogen atom (e.g., fluorine, chlorine,bromine, iodine), nitro group, cyano group, lower alkyl group optionallysubstituted by 1 to 5 halogen atoms (e.g., fluorine, chlorine, bromine,iodine), lower alkoxy group optionally substituted by 1 to 5 halogenatoms (e.g., fluorine, chlorine, bromine, iodine), and the like.

Examples of the lower alkyl group include C₁₋₆ alkyl group such asmethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, pentyl, hexyl etc., and the like, particularly methyl, ethyland the like are preferable. Examples of the lower alkoxy group includeC₁₋₆ alkoxy group such as methoxy, ethoxy, n-propoxy, isopropoxy,n-butoxy, isobutoxy, sec-butoxy, tert-butoxy etc., and the like,particularly preferably methoxy, ethoxy and the like. These substituentsare the same or different and preferably present in the number of 1 or 2or 3 (preferably 1 or 2).

The “N,N-disubstituted carbamoyl group” means a carbamoyl group having 2substituents on the nitrogen atom, wherein one of the substituents isexemplified by those similar to the substituent of the above-mentioned“N-monosubstituted carbamoyl group”, and the other substituent isexemplified by lower alkyl group (e.g., C₁₋₆ alkyl group such as methyl,ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl etc., and thelike), C₃₋₆ cycloalkyl group (e.g., cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and the like), C aralkyl group (e.g., benzyl,phenethyl etc., preferably phenyl-C₁₋₄ alkyl group etc.) and the like.Two substituents may form a cyclic amino group together with a nitrogenatom, and examples of the cyclic aminocarbamoyl group in this caseinclude 1-azetidinylcarbonyl, 1-pyrrolizinylcarbonyl,piperidinocarbonyl, morpholinocarbonyl, 1-piperazinylcarbonyl and 3 to8-membered (preferably 5 or 6-membered) cyclic aminocarbonyl such as1-piperazinylcarbonyl optionally having, at the 4-position, lower alkylgroup (e.g., C₁₋₆ alkyl group such as methyl, ethyl, propyl, isopropyl,butyl, tert-butyl, pentyl, hexyl etc., and the like), aralkyl group(e.g., C₇₋₁₀ aralkyl group such as benzyl, phenethyl etc., and thelike), aryl group (e.g., C₆₋₁₀ aryl group such as phenyl, 1-naphthyl,2-naphthyl etc., and the like), and the like, and the like.

Examples of the “acyl group derived from sulfonic acid” as a substituentinclude one obtained by bonding the one substituent that theaforementioned “N-monosubstituted carbamoyl group” has on the nitrogenatom to sulfonyl, and the like. Preferably, it is an acyl such as C₁₋₆alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl etc.).

Examples of the “acyl group derived from carboxylic acid” as asubstituent include one obtained by bonding hydrogen atom or the onesubstituent that the aforementioned “N-monosubstituted carbamoyl group”has on the nitrogen atom to the carbonyl, and the like. Preferably, itis an acyl such as C₁₋₆ alkanoyl (e.g., formyl, acetyl, propionyl,pivaloyl etc.), benzoyl and the like.

As R¹³ and R¹⁴, alkyl groups and cycloalkyl groups are preferable.Particularly preferably, a compound substituted by either tert-butyl or1-adamantyl and methyl on the ring A of compound (V) is subjected to anasymmetric hydrogenation reaction. In addition, these groups may besubstituted by the above-mentioned substituents. That is, a compoundrepresented by the chemical formula:

is preferable, particularly, a compound represented by

is preferable.

Of the compounds represented by the formulas (IIa), (II), (V), (VI) and(VII), a compound having an acidic group or basic group may form a salt.When a compound has an acidic group, it may form a salt with, forexample, a metal (e.g., sodium, potassium, calcium etc.) or an ammoniumion. When it has a basic group, the compound may form an acid additionsalt, such as an inorganic acid salt (e.g., hydrochloride, sulfate,hydrobromate, phosphate etc.), an organic acid salt (e.g., acetate,trifluoroacetate, succinate, maleate, fumarate, propionate, citrate,tartrate, lactate, oxalate, methanesulfonate, p-toluenesulfonate etc.)and the like.

Throughout the specification, of the compounds shown by the formulas(I), (IIa), (II), (V), (VI) and (VII), and salts thereof are referred toas compound (symbol of formula). For example, a compound of formula (I)and a salt thereof are sometimes simply referred to as compound (I).

According to the method of the present invention (1), compound (I) andan optically active form of compound (II) or (III) (hereinaftersometimes to be referred to as a resolution reagent) are reacted in asuitable solvent to give a diastereomer salt of compound (IVb) or (IVb).The compound (I) may be a racemate containing equivalent amounts of an(S)-compound and an (R)-compound, or a mixture containing either opticalisomer in an amount exceeding the equivalent amount. The opticallyactive form of compound (II) and (III) includes an (S)-compound and an(R)-compound.

The amount of the resolution reagent to be used is preferably 0.1-2times, preferably 0.6-1.2 times, the mol amount relative to compound(I). In this case, mineral acid such as hydrochloric acid, sulfuricacid, phosphoric acid and the like, or organic acid such as acetic acid,propionic acid, fumaric acid, maleic acid and the like may be co-usedwith the resolution reagent to achieve said molar ratio. Two or moreresolution reagents may be used simultaneously.

The solvent to be used is preferably one that dissolves compound (I) andresolution reagent, does not chemically change these compounds and inwhich one of the produced diastereomer salt is sparingly soluble. Forexample, water, alcohols such as methanol, ethanol, isopropanol etc.,ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran,tetrahydropyran etc., ketones such as acetone, 2-butanone etc., andnitriles such as acetonitrile etc., which may be used alone or incombination of two or more kinds thereof. The amount to be used isgenerally 1 to 100-fold amount, preferably 1 to 50-fold amount, relativeto (I). The temperature is generally within the range of not less than15° C. and not higher than the boiling point of the solvent used.

After forming a diastereomer salt, cooling or concentration allowscrystallization of either salt. Depending on the conditions, standing atroom temperature without cooling or concentration may result in easyprecipitation of a sparingly soluble salt.

The crystallized salt can be easily separated by a general solid-liquidseparation method such as filtration, centrifugal separation and thelike. The crystals of the separated salt can be made to have a highpurity as necessary by a method known per se such as recrystallizationand the like.

The mother liquor after separation of a sparingly soluble salt maycontain, as it is, an easily soluble salt alone and as it is or may becooled after concentration to separate an easily soluble salt.

The thus-obtained salt can be decomposed by any known method. Forexample, a treatment with an alkali or acid in a water-soluble solutionachieves the object. Examples of the alkali include hydroxide of alkalimetal or alkaline earth metal such as sodium hydroxide, potassiumhydroxide, calcium hydroxide, barium hydroxide and the like, alkalimetal carbonate or hydrogen carbonate such as sodium carbonate,potassium carbonate, sodium hydrogen carbonate, potassium hydrogencarbonate and the like, and organic base such as ammonia, pyridine andthe like. Examples of the acid include mineral acid such as hydrochloricacid, sulfuric acid, phosphoric acid and the like, and organic acidssuch as trifluoroacetic acid, trifluoromethanesulfonic acid and thelike. Generally, the salt can be treated with a water-soluble base suchas aqueous sodium hydroxide solution, aqueous potassium hydroxidesolution, aqueous ammonia solution and the like and the liberatedoptically active naphthalene derivative is subjected to, for example, asolid-liquid separation such as filtration and centrifugal separation,or extraction step with an organic solvent and the like to give anoptically active form of the objective compound (I). The treatment witha base is generally carried out at about −10 to 25° C. and the amount ofthe base to be used is 1 to 5-fold molar amount relative to salt. Thebase concentration is 1-50 wt %, preferably 5-20 wt %.

When a basic aqueous layer after extraction of a naphthalene derivativeis made acidic with an acid such as hydrochloric acid, sulfuric acid andthe like, an optically active form of compound (II) or an opticallyactive form of compound (III) used as a resolution reagent may berecovered and used again.

A naphthalene derivative represented by the formula (I), which is usedas a starting material in the present invention, can be producedaccording to the method described in the following.

wherein X¹ is a halogen atom such as chlorine, bromine, iodine and thelike, M is a metal atom (lithium, magnesium, metal halide such asmagnesium chloride, magnesium bromide etc., and the like, L is a leavinggroup [C₁₋₆-alkylsulfonyloxy group (e.g., methylsulfonyloxy,ethylsulfonyloxy etc.), C₆₋₁₀ arylsulfonyloxy group (e.g.,benzenesulfonyloxy, ortho-, meta-, or para-toluenesulfonyloxy, ortho-,meta-, or para-nitrobenzenesulfonyloxy and the like), R^(2a) is a loweralkyl group optionally having substituents, R′ is an optionallysubstituted nitrogen-containing heterocyclic group having a protectinggroup, and other symbols are as defined above.

The optionally substituted nitrogen-containing heterocyclic group of the“optionally substituted nitrogen-containing heterocyclic group having aprotecting group” represented by R′ is the same as those represented byR above, and examples of the protecting group are as mentioned below.

The compound (IXa) is reacted with alkyl lithium, metal magnesium andthe like to convert the compound to an organic metal compound (IXb), andthen subsequently reacted with aldehyde compound (Xb) or (Xa) to givecompound (XIa) or (XIb), respectively. Examples of the alkyl lithium tobe used include C₁₋₄ alkyl lithium such as n-butyl lithium, s-butyllithium and the like. The amount of use thereof is 1 mol to 3-fold molaramount, preferably 1 to 1.5-fold molar amount, relative to 1 mol of thestarting material compound (IXa). The reaction temperature at whichalkyl lithium is reacted is from −100° C. to 0° C., preferably from −80°C. to −20° C. When metal magnesium is to be reacted, the reactiontemperature is −20° C. to 100° C., preferably 10° C. to 50° C. Thereaction time is from about 5 minutes to 20 hours. This reaction isgenerally carried out in an organic solvent inert to the reaction.Examples of the organic solvent that does not adversely affect thereaction include ethers such as diethyl ether, dioxane, tetrahydrofuran(THF) and the like, saturated hydrocarbons such as hexane, pentane andthe like, halogenated hydrocarbons such as dichloromethane, chloroformand the like, aromatic hydrocarbons such as benzene, toluene and thelike, and the like, which are used in admixture of one or more kindsthereof at a suitable mixing ratio. The aldehyde compound (Xb) or (Xa)is used in an amount of 0.5 equivalent amount to 10 equivalent amounts,preferably 0.5 to 1.5 equivalent amount, relative to compound (IXb).

The compound (XIa) and (XIb) are alkylated by a conventional method togive compound (XIc) and (Ia), respectively. The alkylation reagent (Xc)to be used is, for example, alkyl halide (e.g., methyl iodide, ethylbromide, isopropyl bromide etc.), alkyl or arylsulfonic acid ester(e.g., methyl methanesulfonate, ethyl p-toluenesulfonate etc.) and thelike. The amount of use thereof is 1 to 10 equivalent amount, preferably1 to 2 equivalent amount, relative to compound (XIa) or (XIb). Thisreaction is generally carried out under basic conditions. Examples ofthe base to be used are sodium hydride, potassium carbonate, sodiummethylate and the like. This reaction is generally carried out in asolvent inert to the reaction. Examples of such solvent include etherssuch as dimethylformamide, tetrahydrofuran and the like, halogenatedhydrocarbons such as dichloromethane and the like, and the like. Whilethe reaction time varies depending on the activity and amount ofalkylating agent, and base, it is generally from 30 minutes to 24 hours,preferably from 30 minutes to 10 hours. The reaction temperature isgenerally from −20° C. to 150° C.

The protecting group of R^(1a) is removed from compound (XIc) by amethod known per se or an analogous method to give compound (Ia). Forexample, when R′ of compound (XIc) has a trityl group, or when anitrogen-containing heterocyclic ring optionally having substituents isprotected by a trityl group, the trityl group can be removed by atreatment under acidic conditions, or hydrogenolysis. Examples of theacid include organic acid such as formic acid, acetic acid and the like,inorganic acid such as hydrochloric acid etc., and the like. It is alsopossible to use a solvent inert to the reaction, such as alcohols,ethers such as THF etc., and the like. The reaction temperature isgenerally from 0° C. to 100° C.

wherein R^(1b) is as defined for R¹ except hydrogen atom, and othersymbols are as defined above.

The compound (XId) can be obtained by subjecting compound (XIa) totypical oxidization reaction. This reaction is generally carried outusing manganese dioxide, chromic acid and the like as an oxidant, in asolvent inert to the reaction, such as dichloromethane, chloroform, THFand the like. The reaction time is generally from about 30 minutes to 48hours, preferably from 30 minutes to 10 hours. The reaction temperatureis generally from 0° C. to 100° C., preferably from 20° C. to 70° C.

The compound (XIe) can be obtained by removing the protecting group fromcompound (XId) by a method known per se or an analogous method. Theprotecting group can be removed according to the method analogous to themethod to obtain compound (Ia) from compound (XIc). Then, compound (XIe)is reacted with an organic metal reagent (Xd) (alkyl lithium reagentsuch as methyllithium etc., Grignard's reagent such as ethylmagnesiumbromide, isopropyl magnesium chloride etc., and the like) to givecompound (Ib). This reaction is generally carried out according to amethod known per se, such as the method described in Shin Jikken KagakuKouza Vol. 14, p. 512 (Maruzen) or a method analogous thereto. In thisreaction, the organic metal reagent (Xd) is used in an amount of 1 to 10equivalents, preferably 1 to 3 equivalents, relative to the ketonecompound (XIe). The reaction temperature is from −100° C. to 50° C.,preferably from −80° C. to 20° C. The reaction time is from about 5minutes to 20 hours. This reaction is carried out in an organic solventgenerally inert to the reaction. Examples of the organic solvent thatdoes not adversely affect the reaction include ethers such as diethylether, dioxane, tetrahydrofuran and the like, saturated hydrocarbonssuch as hexane, pentane and the like, halogenated hydrocarbons such asdichloromethane, chloroform and the like, aromatic hydrocarbons such asbenzene, toluene and the like, and the like, which may be used alone orin combination of 2 or more kinds thereof.

The compound (Ib) can be also synthesized by reacting compound (XId)with compound (Xd) to give compound (XIf), which is followed bydeprotection.

wherein R⁰ is a group represented by OR″ or NR″R′″ (R″ and R′″ are eachC₁₋₆ alkyl group, or C₁₋₆ alkyloxy group and NR″R′″ includes cyclicamine residue such as morpholino group, pyrrolidino group and the like),R^(1a) is a nitrogen-containing heterocyclic group optionally havingsubstituents, which may have protecting group, and other symbols are asdefined above.

Of the above-mentioned nitrogen-containing heterocyclic group optionallyhaving substituents and protecting group, which is represented byR^(1a), the group having a protecting group is the same as thosementioned with regard to the aforementioned R′, and the group not havinga protecting group is the same as those mentioned with regard to theaforementioned R.

The compound (XIg) and compound (Xe) are reacted according toFriedel-Crafts reaction known per se, for example, the method describedin Shin Jikken Kagaku Kouza Vol. 14, p. 511 (Maruzen) or a methodanalogous thereto to give carbonyl compound (XIh). The compound (XIh)can be also synthesized by reacting compound (XIj) with compound (Xg).In this reaction, a solvent inert to the reaction, such as THF,dichloromethane and the like, is used and the compound (XIj) is used inan amount of 0.2-2 equivalents, preferably 0.2-1.5 equivalents, relativeto compound (Xg). The reaction temperature is from −80° C. to 50° C.,preferably from −80° C. to 20° C.

The compound (XIh) is alkylated using compound (Xf) to give compound(XIf). This reaction can be carried out according to the reaction tosynthesize compound (Ib) from compound (XIe).

When organic metal reagent (IXb) is reacted with ketone compound (Xh)according to a method analogous to the method for synthesizing compound(Ib) from compound (XIe), compound (XIf) can be synthesized. When thenitrogen-containing heterocyclic ring of compound (XIf) is protected,the protecting group is removed according to a method analogous to themethod for synthesizing compound (Ia) to give compound (Ib).

wherein each symbol in the formula is as defined above.

The compound (XIf) is alkylated with (Xc) to give compound (XIk) and theprotecting group is removed to give compound (Ic). The alkylation can becarried out according to a method analogous to the method forsynthesizing compound (XIc) from compound (XIb). The protecting groupcan be removed according to a method analogous to the method forsynthesizing compound (Ia) from compound (XIc).

Both the (S)-compound and (R)-compound of the optically active compoundrepresented by the formula (II) can be produced according to a knownmethod, such as the method described in The Journal of OrganicChemistry, Vol. 50, pp. 4508-4541 (1985).

The optically active compound represented by the formula (III) can beprepared according to a known method, such as the method described inJP-B-55-47013.

An optically active form of the compound (I) has a superior effect as apharmaceutical agent, and especially has a superior inhibitory activityagainst steroid C_(17,20)-lyase. The compound (I) is low toxic andcauses few side effects. Therefore, compound (I) is useful as, forexample, an agent for the prophylaxis or treatment of various diseases,such as (1) primary cancer of malignant tumor (e.g., prostate cancer,breast cancer, uterine cancer, ovarian cancer etc.), and metastasis orrecurrence thereof, (2) various symptoms accompany these cancers (e.g.,pain, cachexia etc.), (3) prostatic hypertrophy, virilism, hirsutism,male pattern alopecia, precocious puberty, endometriosis, uterus myoma,adenomyosis of uterus, mastopathy, polycystic ovary syndrome etc. in amammal (e.g., human, bovine, horse, dog, cat, monkey, mouse, rat etc.,especially human).

While an optically active form of compound (I) has a superior effecteven when used solely, the effect can be further promoted by using thecompound in combination with other pharmaceutical preparations andtherapies. Examples of the preparation and therapy to be combinedinclude, but are not limited to, sex hormones, alkylating agents,antimetabolites, antitumor antibiotics, plant alkaloids, immunotherapiesand the like.

Examples of other therapy include operation, thermotherapy, radiotherapyand the like.

Together with the chemotherapy including administration of compound (I),therapies other than chemotherapies, such as an operation includingorchidectomy, thermotherapy, radiotherapy and the like can be conducted.

Examples of the pharmaceutically acceptable carrier include variousorganic or inorganic carriers conventionally used as materials forpharmaceuticals, which are added in suitable amounts as excipients,lubricants, binders, disintegrators, thickeners for solid preparations;solvents, dispersants, solubilizing agents, suspending agents, isotonicagents, buffer agents, soothing agents for liquid preparations, and thelike. Where necessary, additives such as preservatives, antioxidants,coloring agents, sweetening agents etc. can be used. Examples ofpreferable excipient include lactose, saccharose, D-mannitol, starch,crystalline cellulose, light anhydrous silicic acid and the like.Examples of preferable lubricant include magnesium stearate, calciumstearate, talc, colloidal silica, and the like. Examples of preferablebinder include crystalline cellulose, saccharose, D-mannitol, dextrin,hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, and the like. Examples of preferable disintegrator includestarch, carboxymethylcellulose, calcium carboxymethylcellulose, sodiumcrosscarmellose, sodium carboxymethyl starch, and the like. Examples ofpreferable thickener include natural rubbers, cellulose derivatives,acrylate polymers, and the like. Examples of preferable solvent includewater for injection, alcohol, propylene glycol, Macrogol, sesame oil,corn oil, and the like. Examples of preferable dispersant include Tween80, HCO 60, polyethylene glycol, carboxymethylcellulose, sodiumalginate, and the like. Examples of preferable solubilizing agentinclude polyethylene glycol, propylene glycol, D-mannitol, benzylbenzoate, ethanol, trisaminomethane, cholesterol, triethanolamine,sodium carbonate, sodium citrate, and the like. Examples of preferablesuspending agent include surfactants, such as stearyl triethanolamine,sodium laurylsulfate, laurylaminopropionic acid, lecithin, benzalkoniumchloride, benzethonium chloride, glycerin monostearate etc.; hydrophilicpolymer such as polyvinyl alcohol, polyvinyl pyrrolidone, sodiumcarboxymethyl cellulose, methylcellulose, hydroxymethylcellulose,hydroxyethylcellulose, hydroxypropylcellulose etc.; and the like.Examples of preferable isotonic agent include sodium chloride, glycerin,D-mannitol and the like.

Examples of preferable buffer agent include buffer solution such asphosphate, acetate, carbonate, citrate etc., and the like. Examples ofpreferable soothing agent include benzyl alcohol, and the like. Examplesof preferable preservative include paraoxybenzoates, chlorobutanol,benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, andthe like. Examples of preferable antioxidant include sulfurous acidsalt, ascorbic acid, and the like.

The pharmaceutical preparation of the present invention can bemanufactured by a conventional method. The ratio of compound (I)contained in a pharmaceutical preparation is usually 0.1 to 100% (w/w).Specific examples are shown below.

(1) Tablets, Powder, Granules, Capsules:

These can be produced by adding, for example, excipients,disintegrators, binders, lubricants etc. to compound (I), compressionforming the mixture and, where necessary, coating for masking of taste,enteric or sustained release.

(2) Injection:

This can be produced by preparing compound (I) into an aqueous injectiontogether with, for example, dispersants, preservatives, isotonic agentsetc., or into an oily injection by dissolving, suspending or emulsifyingthe compound in a vegetable oil such as olive oil, sesame oil, cottonseed oil, corn oil etc., or propylene glycol etc.

The content of compound (I) admixed in these preparations is usually0.01 to 50%, though subject to change depending upon the kind ofpreparations.

While the amount of compound (I) to be contained in the above-mentionedpharmaceutical preparation varies depending upon the compound selected,the kind of animal to be the administration target, administrationfrequency and the like, the compound proves effective over a broadrange. The daily dose of the pharmaceutical preparation of the presentinvention as an effective amount of compound (I) of the presentinvention, for example, for in the case of oral administration to anadult patient with a solid tumor (e.g., patient with prostate cancer) isgenerally about 0.001 to about 500 mg/kg body weight, preferably about0.1 to about 40 mg/kg body weight, more preferably about 0.5 to about 20mg/kg body weight. When the compound is parenterally administered oradministered concurrently with a different anticancer agent, the dosegenerally becomes less than those mentioned above. The amount of thecompound actually administered is determined according to the selectionof compound, dosage form of each preparation, age, body weight and sexof patient, degree of disease, administration route, period andintervals of administration and the like, which can be varied accordingto the judgment of a doctor.

The administration route of the aforementioned pharmaceuticalpreparation is free of any particular limitation by various conditions.The preparation can be administered, for example, orally orparenterally. Examples of the “parenteral” used here includeintravenous, intramuscular, subcutaneous, intranasal, intradermal,instillation, intracerebral, intrarectal, intravaginal andintraperitoneal administrations, and the like.

The above-mentioned administration term and administration interval varydepending upon various conditions and determined any time by judgment ofa doctor. Divided administration, consecutive administration,intermittent administration, high dose short period administration,repeat administration and the like can be employed. For oraladministration, for example, the dose is desirably given once a day ordivided into several portions (especially two or three doses a day) andadministered. Administration of a sustained release preparation orintravenous drip infusion over a long time is also possible.

The compound (IIa) can be produced according to the methods shown in thefollowing Production method 1, Production method 2 and Production method3. The starting material compound and synthetic intermediate can besubjected to a reaction in the form of a free compound or a salt likecompound (IIa), or as a reaction mixture, or after isolation accordingto a known method.

Production Method 1

First, compound (V) is subjected to asymmetric hydrogenation reaction togive an optically active form, which is then reduced and the obtainedcompound (VII) is subjected to phosphorylation to give the objectivecompound.

Production of compound (VI) by asymmetric hydrogenation of compound (V)is performed by hydrogenation in the presence of a complex of anoptically active ligand and ruthenium.

A preferable embodiment usable as the optically active ligand in thisreaction is bidentate phosphine. As a specific example thereof,structural formulas of one of the optical isomers are shown.

wherein each symbol is as defined above.

Preferably, it is compound (VI) abbreviated as BisP*.

The compound (VIII) exemplified in the above formulas can be producedaccording to the method described in Journal of the American ChemicalSociety, Vol. 117, p. 4423 (1995).

For example, the ruthenium complex of compound (VIII) can be obtained byheating compound (VIII) and, for example, 1,5-cyclooctadieneruthenium(2-methylallyl) and the like, in a solvent such as hexane, filtrationand concentration to give a solid, which is dissolved again in acetoneand the like and treated with hydrobromic acid and the like.

In this reaction, the use of a ruthenium complex of compound (VIII) ispreferable. As long as an optically active hydroxy compound can beproduced from a keto compound, however, a complex with a transitionmetal other than ruthenium can be used.

This reaction is carried out generally under pressurization with ahydrogen gas. The hydrogen pressure is generally applied at 0.1 to about100 kg/cm², preferably about 1 to about 10 kg/cm². This-reaction ispreferably carried out in a solvent. The solvent may be any as long asit does not inhibit the reaction and is exemplified by hydrocarbons suchas hexane, pentane and the like, amides such as N,N-dimethylformamide,N,N-dimethylacetamide and the like, aromatic hydrocarbons such asbenzene, toluene and the like, aliphatic esters such as ethyl acetate,propyl acetate and the like, ethers such as diethyl ether, diisopropylether, tetrahydrofuran and the like, halogenated hydrocarbons such asdichloromethane, chloroform and the like, alcohols such as methanol,ethanol, 2-propanol and the like, sulfoxides such as dimethyl sulfoxideand the like, nitriles such as acetonitrile and the like, water and thelike. These solvents can be used alone or as a mixed solvent.Particularly preferably, a mixed solvent of methanol and water is used.The amount of the solvent to be used is generally about 1 to about1000-fold volume, preferably about 5 to about 100-fold volume, relativeto compound (V). The reaction temperature is about 0 to about 200° C.,preferably about 10 to about 100° C. The reaction time is from about 10minutes to about 100 hours, preferably from about 1 hour to about 50hours. The amount of the ruthenium complex of compound (Xi) to be usedis generally about 1/1 to about 1/100,000-fold mol, preferably about1/10 to about 1/10,000-fold mol, relative to compound (V). The compound(VI) thus obtained can be isolated and purified by a method known perse, such as extraction, pH adjustment, phase transfer, salting-out,crystallization, chromatography and the like. It is also possible tosubject the compound as a crude product in the next step.

The compound (VI) can be converted to compound (VII) by reduction. Thisreaction is carried out according to a method known per se.

The reducing agent includes, for example, metal hydrides such as sodiumborohydride, lithium borohydride, lithium aluminum hydride, diisopropylaluminum hydride, triethyl lithium borohydride and the like, diborane,9-BBN, catechol borane and the like. The solvent includes, for example,aromatic hydrocarbons such as benzene, toluene, xylene and the like,ethers such as diethyl ether, diisopropyl ether, butylmethyl ether,dioxane, tetrahydrofuran and the like, halogenated hydrocarbons such aschloroform, dichloromethane, ethylene dichloride, carbon tetrachlorideand the like, and the like. Depending on the kind of reducing agent,alcohols such as methanol, ethanol, propanol, butanol and the like canbe used. Of these, ethers such as diethyl ether, tetrahydrofuran and thelike are particularly preferable. These reducing agents are preferablyused in an amount of 0.25-10 molar equivalents relative to compound(VI). Preferably, this reaction is generally carried out from −20 to100° C., more preferably from 0 to 100° C., for 0.5 hour to 50 hours,preferably from 0.5 hour to 24 hours. The compound (VIII) thus obtainedcan be isolated by separation and purification means known per se, suchas concentration, solvent extraction, crystallization, phase transfer,chromatography and the like.

The compound (VII) can be advantageously converted to compound (IIa) by,for example, reaction with phosphoryl chloride, and then alkalinehydrolysis, and neutralization with an acid, as shown in the followingformulas.

wherein each symbol is as defined above.

The amount of phosphoryl chloride to be used is 1-5 molar equivalents,preferably 1-2 molar equivalents, relative to compound (VII). Thesolvent includes, for example, aromatic hydrocarbons such as benzene,toluene, xylene and the like, ethers such as diethyl ether, diisopropylether, butylmethyl ether, dioxane, tetrahydrofuran and the like,halogenated hydrocarbons such as chloroform, dichloromethane, ethylenedichloride, carbon tetrachloride and the like, and the like.Particularly preferably, halogenated hydrocarbons such asdichloromethane and the like are used. This reaction is carried out atgenerally from 0 to 150° C., preferably from 20 to 100° C., for 0.5 hourto 50 hours, preferably from 0.5 hour to 10 hours. The chlorides ofphosphoric acid thus obtained can be isolated by a separation andpurification means known per se, such as concentration, solventextraction, crystallization, phase transfer, chromatography and thelike. It is also possible to subject the compound to the next hydrolysisstep as a crude product. The hydrolysis is carried out in the presenceof a base, preferably alkali metal hydroxide, sodium hydroxide,potassium hydroxide and the like. The amount of the base to be used is 1to 20 molar equivalents, preferably 1 to 5 molar equivalents, relativeto compound (VII). The solvent includes, for example, aromatichydrocarbons such as benzene, toluene, xylene and the like, ethers suchas diethyl ether, diisopropyl ether, butylmethyl ether, dioxane,tetrahydrofuran and the like, halogenated hydrocarbons such aschloroform, dichloromethane, ethylene dichloride, carbon tetrachlorideand the like, alcohols such as methanol, ethanol and the like, water andthe like. Particularly preferably, it is water. These may be used aloneor as a mixed solvent. This reaction is carried out generally from 0° C.to 200° C., preferably from 50° C. to 150° C., for 0.1 hour to 50 hours,preferably from 0.1 hour to 2 hours.

Neutralization can be performed by adding an acid, such as hydrochloricacid, hydrobromic acid, sulfuric acid and the like. The compound (IIa)thus obtained can be isolated according to a separation and purificationmeans known per se, such as concentration, solvent extraction,crystallization, phase transfer, chromatography and the like.

When, of the compounds (V), R¹⁰ and R¹¹ in combination show an alkylenegroup optionally having substituents, these compounds can be producedby, as shown in the following formula, reacting compound (V′) whereinboth R¹⁰ and R¹¹ are hydrogen atoms with compound (Xi) to cycloalkylatethe alpha-position carbon of the beta-ketoester.

As shown below

wherein X¹ and X² are the same or different and each is a halogen atom,C₁₋₆ alkylsulfonyloxy group or C₆₋₁₀ arylsulfonyloxy group, and othersymbols are as defined above, the compound can be produced bycycloalkylating the alpha-position carbon of the beta-ketoesteraccording to a method known per se.

In the above-mentioned formulas, halogen atom represented by X² isexemplified by chlorine, bromine and iodine, C₁₋₆ alkylsulfonyloxy groupis exemplified by methylsulfonyloxy, ethylsulfonyloxy and the like , andC₆₋₁₀ arylsulfonyloxy group is exemplified by benzenesulfonyloxy,ortho-, meta-, or para-toluenesulfonyloxy, ortho-, meta-, orpara-nitrobenzenesulfonyloxy group and the like.

Production Method 2

Using compound (V) as a starting material, the series of the followingreactions are carried out to synthesize racemate compound (IIa), whichis optically resolved to advantageously give the compound.

wherein each symbol is as defined above.

That is, compound (V) is reduced to give a diol compound, which is thensubjected to phosphorylation to give racemate compound (II′), which isthen subjected to optical resolution to give an optically active isomer.

The first step of this production method is performed according to amethod known per se. The reducing agent is exemplified by metal hydridessuch as sodium borohydride, lithium borohydride, lithium aluminumhydride, diisopropyl aluminum hydride, triethyl lithium borohydride andthe like, and boranes such as diborane, catecholborane, 9-BBN and thelike. The solvent is exemplified by aromatic hydrocarbons such asbenzene, toluene, xylene and the like, ethers such as diethyl ether,diisopropyl ether, butylmethyl ether, dioxane, tetrahydrofuran and thelike, and halogenated hydrocarbons such as chloroform, dichloromethane,ethylene dichloride, carbon tetrachloride and the like. Alcohols such asmethanol, ethanol, propanol and the like may be used in some cases.Preferably, ethers such as diethyl ether, tetrahydrofuran and the likeare used. These reducing agents are use in amount of 0.5-10 molarequivalents, preferably 0.5-2 molar equivalents, relative to compound(V). This reaction is generally carried out from −20° C. to 100° C.,preferably from 0° C. to 100° C., for 0.5 hour to 100 hours, preferablyfrom 0.1 hour to 24 hours. The diol compound thus obtained can beisolated by a separation and purification means known per se, such asconcentration, solvent extraction, crystallization, phase transfer andchromatography. It is also possible to use the compound as a crudeproduct as a starting material for the next step.

The phosphorylation step of compound (VII) can be carried out in thesame manner as in phosphorylation of the aforementioned compound (VII).

The next step is optical resolution. The optical resolution of theobtained racemate cyclic phosphoric acid (dioxaphosphorinan) can becarried out by liquid chromatography using an optically active column,or by introducing into a diastereomer by the reaction with an opticallyactive alcohol and separation by physical means, or by forming adiastereomer salt by reaction with an optically active amino compoundand separation by physical means. Of these, a method for forming adiastereomer salt as shown in the following formulas is particularlypreferable.

wherein each symbol is as defined above.

The optically active amino compound used to form a diastereomer saltcannot be specified because it varies depending on compound (IIa) andeach compound. For example, it includes (−)-ephedrine, (+)-cinchonine,(−)-cinchonine, (+)-quinidine, (−)-quinidine, (+)-dehydroabiethylamine,(+)-2-amino-1-phenyl-1,3-propanediol,(−)-2-amino-1-phenyl-1,3-propanediol, (−)-(parahydroxyphenyl)glycine,(+)-phenylethylamine, (−)-phenylethylamine, (+)-tolylethylamine,(−)-tolylethylamine, (+)-(1-naphthyl)ethylamine,(+)-cyclohexylethylamine, (−)-cyclohexylethylamine, (+)-prolinol, andamino acid ester.

For mutual separation of diastereomer salts, crystallization andsubsequent filtration are generally used, wherein each salt is obtainedfrom crystals and mother liquor.

The salt obtained as crystals and the salt obtained by concentration ofthe mother liquor are each independently treated with acid to give anoptically active compound (IIa). The acid to be used for this purposeincludes, for example, hydrochloric acid, hydrobromic acid, sulfuricacid, phosphoric acid and the like, with preference given tohydrochloric acid. This reaction is preferably carried out in a solvent,more preferably in water.

To improve the chemical purity or optical purity of the obtainedcompound (IIa), recrystallization can be performed.

Production Method 3

Moreover, compound (IIa) can be advantageously produced according to,for example, the method described in Journal of Organic Chemistry, Vol.50, p. 4508 (1985) and using aldehyde as a starting material by thefollowing series of reactions to synthesize a racemate compound (IIa),which is then subjected to optical resolution.

wherein each symbol is as defined above.

That is, by Aldol Canizzaro reaction of aromatic aldehyde andcycloalkylaldehyde to give a diol compound, which is then subjected tophosphorylation to give a racemate compound (IIa), followed by opticalresolution thereof, an optically active isomer can be produced.

The first step in this Production method 3 is an Aldol Canizzaroreaction of aromatic aldehyde and cycloalkylaldehyde generally using 2molar equivalents of cycloalkylaldehyde relative to aromatic aldehyde.This reaction is carried out as appropriate in a solvent in the presenceof a base.

The base is exemplified by alkali metal alkoxides such as sodiummethoxide, sodium ethoxide and the like, inorganic bases such aspotassium carbonate, sodium carbonate and the like, alkali metalhydroxides such as sodium hydroxide, potassium hydroxide and the like,alkali metal hydrides such as sodium hydride, potassium hydride and thelike, alkali metal carboxylates such as sodium acetate and the like,secondary amines such as piperidine, piperazine, pyrrolidine,morpholine, diethylamine and the like, and pyridines such as pyridine,dimethylaminopyridine and the like. Preferably, alkali metal hydroxidessuch as sodium hydroxide, potassium hydroxide and the like are used. Theamount of these bases to be used is preferably 1 to 5 molar equivalentsrelative to aromatic aldehyde.

The solvent is exemplified by alcohols such as methanol, ethanol,propanol, butanol and the like, aromatic hydrocarbons such as benzene,toluene, xylene and the like, ethers such as diethyl ether, diisopropylether, butylmethyl ether, dioxane, tetrahydrofuran and the like,halogenated hydrocarbons such as chloroform, dichloromethane, ethylenedichloride, carbon tetrachloride and the like, N,N-dimethylformamide,dimethyl sulfoxide and the like. Preferably, alcohols such as methanol,ethanol and the like are used. The amount of the solvent to be used is 1to 50-fold (v/w), preferably 1 to 10-fold (v/w), relative to aromaticaldehyde.

This reaction is generally carried out from 0° C. to 100° C., preferablyfrom 0° C. to 100° C., for 0.5 hour to 50 hours, preferably for 0.5 hourto 24 hours.

The compound (VIIa) thus obtained can be isolated by a separation andpurification means known per se, such as concentration, solventextraction, crystallization, phase transfer, chromatography and thelike. Alternatively, the compound can be used in the next step as acrude product.

The obtained diol compound can be converted to an optically active form(dioxaphosphorinan) or a compound represented by compound (IIa)according to the method described in the above-mentioned Productionmethod 2.

An optically active form of compound (II) of the present inventionresolves optically active isomers of various amino compounds, which areuseful for the production of pharmaceutical agents, agriculturalchemicals, liquid crystals and a starting material thereof and the like,and can be used as a reagent for optical resolution. For example, asdescribed in Examples 2 and 8, the compound can be used as a reagent foroptical resolution of1-(6,7-dimethoxynaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol,and1-(1H-imidazol-4-yl-1-(6-methoxynaphthalen-2-yl)-2-methyl-1-propanol.

BEST MODE FOR EMBODIMENT OF THE INVENTION

The present invention is explained in detail in the following byreferring to Reference Examples and Examples, which are not to beconstrued as limitative.

The nuclear magnetic resonance spectrum (¹H-NMR) was measured by JEOL.Ltd, JMTCO400/54 (400 MHz) or Hitachi, Ltd., R-90H (90 MHz) usingtetramethylsilane as an internal standard. The δ values are shown inppm. The symbols in Reference Examples mean the following.

s: singlet, d: doublet, t: triplet, m: multiplet, br: broad, J: couplingconstant.

The infrared absorption spectrum (IR) was recorded using Paragon 1000manufactured by Perkin-Elmer Corporation, according to KBr method.

enantiomer excess (% ee) and diastereomer excess (% de) were measured byhigh performance liquid chromatography.

high performance liquid chromatography (Condition A)

column: SUMICHIRAL OA-3300 4.6×250 mm (SUMIKA CHEMICAL ANALYSIS SERVICE,LTD.)

mobile phase: 0.05M ammonium acetate—ethanol solution

flow rate: 0.3 ml/min

detection: UV (254 nm)

temperature: room temperature

high performance liquid chromatography (Condition B)

column: CHIRALPAK AD (DAICEL CHEMICAL INDUSTRIES, LTD.)

mobile phase: hexane/ethanol 85:15

flow rate: 1.0 ml/min.

detection: UV 254 nm

temperature: room temperature.

high performance liquid chromatography (Condition C)

column: CHIRALCEL OD-RH (DAICEL CHEMICAL INDUSTRIES, LTD.)

mobile phase: 0.1 M aqueous potassium hexafluorophosphate

solution: acetonitrile 70:30

flow rate: 0.5 ml/min.

detection: UV 254 nm

temperature: room temperature.

high performance liquid chromatography (Condition D)

column: CHIRALPAK AD (DAICEL CHEMICAL INDUSTRIES, LTD.)

mobile phase: hexane/ethanol/diethylamine 85:15:0.1

flow rate: 1.0 ml/min.

detection: UV 254 nm

temperature: room temperature.

high performance liquid chromatography (Condition E)

column: SUMICHIRAL OA-4700, 2 columns (SUMIKA CHEMICAL ANALYSIS SERVICE,LTD.)

mobile phase: 0.12 M ammonium acetate/methanol (4/1)

flow rate: 0.5 ml/min

detection: UV (240 nm).

temperature: room temperature.

high performance liquid chromatography (Condition F)

column: CHIRALCEL OD (DAICEL CHEMICAL INDUSTRIES, LTD.)

mobile phase: hexane/2-propanol (95/5)

flow rate: 0.5 ml/min

detection: UV (220 nm)

temperature: room temperature.

REFERENCE EXAMPLE 1 Production of1-(1H-imidazol-4-yl)-1-(6-methoxynaphthalen-2-yl)-2-methylpropanol

(i) Production of(6-methoxynaphthalen-2-yl)-(1-trityl-1H-imidazol-4-yl)methanol

2-Bromo-6-methoxynaphthalene (30 g) was dissolved in THF (400 ml) andcooled to −78° C. A solution (1.6 M; 99 ml) of n-butyl lithium in hexanewas added dropwise, and the mixture was stirred at −78° C. for 30 min. Asolution (300 ml) of 4-formyl-1-trityl-1H-imidazol (38.9 g) in THF wasslowly added dropwise. After stirring at −78° C. for 30 min, thereaction mixture was poured into 3% aqueous citric acid solution (600ml). The organic layer was separated and the aqueous layer was extractedwith ethyl acetate. The organic layer was combined and the mixture waswashed with saturated brine, dried and concentrated. The residue waswashed with ethyl acetate to give the title compound (35.0 g) as acolorless solid.

¹H-NMR (CDCl₃) δ: 3.90 (3H, s), 5.89 (1H, s), 6.60 (1H, d, J=1.4 Hz),7.08-7.15 (8H, m), 7.26-7.34 (9H, m), 7.42-7.47 (2H, m), 7.63-7.69 (2H,m), 7.78 (1H, s).

IR (KBr): 3166, 1603, 1478, 1451, 1260, 1171, 1128, 754, 702 cm⁻¹.

(ii) Production of(6-methoxynaphthalen-2-yl)-(1-trityl-1H-imidazol-4-yl)ketone

(6-methoxynaphthalen-2-yl)-(1-trityl-1H-imidazol-4-yl)methanol (18.0 g)was dissolved in chloroform (300 ml) and manganese dioxide (56 g) wasadded. The mixture was heated under reflux for 1 h. The reaction mixturewas filtrated and concentrated. To the residue was added ether and themixture was crystallized to give the title compound (17.0 g) as acolorless solid.

¹H-NMR (CDCl₃) δ: 3.94 (3H, ), 7.15-7.23 (8H, m), 7.34-7.40 (9H, m),7.58 (1H, d, J=1.3 Hz), 7.78 (1H, d, J=1.3 Hz), 7.78 (1H, d, J=8.6 Hz),7.86 (1H, d, J=9.6 Hz), 8.26 (1H, dd, J=8.6, 1.6 Hz), 8.95 (1H, 9).

IR (KBr): 1620, 1520, 1493, 1480, 1445, 1265, 1196, 1179, 909, 872, 747,733, 702 cm⁻¹.

(iii) Production of (1H-imidazol-4-yl)-(6-methoxynaphthalen-2-yl)ketone

(6-Methoxynaphthalen-2-yl)-(1-trityl-1H-imidazol-4-yl)ketone (15.0 g)was dissolved in THF (80 ml) and 90% formic acid (20 ml) was added. Themixture was stirred at 50° C. for 2 h and the solvent was evaporated. 1NHydrochloric acid (60 ml) was added and the precipitate was filtrated.The filtrate was washed with ether and neutralized with potassiumcarbonate. The resulting precipitate was collected by filtration anddried under reduced pressure to give the title compound (7.54 g) as acolorless solid.

¹H-NMR (CDCl₃+CD₃OD) δ: 3.97 (3H, s), 7.26-7.21 (2H, m), 7.78 (1H, s),7.82-7.91 (3H, m), 7.99 (1H, dd, J=8.5, 1.7 Hz), 8.49 (1H, 5).

IR (KBr): 1636, 1624, 1481, 1346, 1264, 1169, 1024, 1005 cm⁻¹.

(iv) Production of1-(1H-imidazol-4-yl)-1-(6-methoxynaphthalen-2-yl)-2-methylpropanol

(1H-Imidazol-4-yl)-(6-methoxynaphthalen-2-yl)ketone (6.50 g) wasdissolved in THF (120 ml) and the mixture was cooled to −10° C. Asolution (2.0 M; 38.7 ml) of isopropyl magnesium chloride in THF wasslowly added dropwise and the mixture was stirred for 30 min. To thereaction mixture was added saturated aqueous solution of ammoniumchloride and the mixture was diluted with water and extracted with ethylacetate. The extract was washed with saturated brine, and after drying,concentrated. The obtained residue was purified by silica gel columnchromatography (eluate, chloroform:methanol=20:1→10:1) andrecrystallized from ethyl acetate to give the title compound (5.04 g) asa colorless crystalline powder.

¹H-NMR (CDCl₃+CD₃OD) δ: 0.81 (3H, d, J=6.8 Hz), 1.00 (3H, d, J=6.8 Hz),2.64-2.78 (1H, m), 3.91 (3H, s), 7.00 (1H, d, J=1.0 Hz), 7.09-7.15 (2H,m), 7.51-7.56 (2H, m), 7.65-7.75 (2H, m), 7.91 (1H, d, J=1.4 Hz).

IR (KBr): 3140, 2984, 2957, 1464, 1222, 1028, 856, 806, 652 cm⁻¹.

REFERENCE EXAMPLE 2 Production of1-(1H-imidazol-4-yl)-1-(6-methoxynaphthalen-2-yl)butanol

By the reaction in the same manner as in Reference Example 1-(iv) using(1H-imidazol-4-yl)-6-methoxynaphthalen-2-ylketone (0.60 g) and asolution (1.0 mol, 2.4 ml) of n-propylmagnesium bromide in THF, thetitle compound (0.53 g) was obtained as a colorless solid.

¹H-NMR (CDCl₃) δ: 0.89 (3H, t, J=7.3 Hz), 1.10-1.30 (1H, m), 1.37-1.55(1H, m), 2.20-2.30 (2H, m), 3.91 (3H, s), 6.90 (1H, s), 7.10-7.15 (2H,m), 7.45 (1H, dd, J=8.6, 1.8 Hz), 7.50 (1H, s), 7.65-7.73 (2H, m), 7.91(1H, s).

IR (KBr): 2955, 1605, 1505, 1483, 1265, 1221, 1167, 1032, 850 cm⁻¹.

REFERENCE EXAMPLE 3 Production of1-(6-ethoxynaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol

(i) Production of(6-ethoxynaphthalen-2-yl)(1-trityl-1H-imidazol-4-yl)ketone

2-Bromo-6-ethoxynaphthalene (5.3 g) was dissolved in THF (40 ml) andmagnesium (0.515 g) and methyl iodide (one drop) were added and themixture was vigorously stirred to dissolve magnesium. The reactionmixture was ice-cooled and a solution of 4-formyl-1-tritylimidazole (7g) in THF (80 ml) was added dropwise over 30 min. The mixture wasstirred at room temperature for 1 h. To the reaction mixture were addedsaturated aqueous solution (40 ml) of ammonium chloride and water (40ml) and the mixture was extracted with ethyl acetate. The extract waswashed with saturated brine, dried over magnesium sulfate andconcentrated. The residue was washed with ethyl acetate to give(6-ethoxynaphthalen-2-yl)-(1-trityl-1H-imidazol-4-yl)methanol (6.3 g) asa colorless powder. This product (6.3 g) was dissolved indichloromethane (120 ml) and manganese dioxide (6 g) was added. Themixture was stirred at room temperature overnight. The reaction mixturewas filtered through Celite and the filtrate was concentrated. Theresidue was crystallized from THF-ethyl acetate to give the titlecompound (5.5 g) as a colorless powder.

¹H-NMR (CDCl₃) d: 1.40 (3H, t, J=7 Hz), 4.08 (2H, q, J=7 Hz), 7.00-7.35(17H, m), 7.47 (1H, d, J=1.4 Hz), 7.60-7.70 (3H, m), 8.15 (1H, d, J=8.8Hz), 8.84 (1H, s).

IR (KBr): 1620, 1520, 1469, 1263, 1182 cm⁻¹.

(ii) Production of1-(6-ethoxynaphthalen-2-yl)-1-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol

(6-Ethoxynaphthalen-2-yl)-(1-trityl-1H-imidazol-4-yl)ketone (3.0 g) wasdissolved in THF (45 ml) and a solution (2 M, 4 ml) of isopropylmagnesium chloride in THF was added dropwise under ice-cooling. Themixture was stirred at room temperature for 30 min and saturated aqueoussolution (20 ml) of ammonium chloride and water (20 ml) were added. Themixture was extracted with ethyl acetate and the extract was washed withsaturated brine, dried and concentrated. The residue was crystallizedfrom ethyl acetate-diisopropyl ether to give the title compound (1.72 g)as a colorless powder. Crystallization mother liquor was purified bysilica gel chromatography (eluate, hexane-ethyl acetate=1:2) to give thetitle compound (0.43 g).

¹H-NMR (CDCl₃) d: 0.75 (3H, d, J=6.8 Hz), 0.94 (3H, d, J=6.8 Hz), 1.47(3H, t, J=7 Hz), 2.40-2.60 (1H, m), 3.64 (1H, s), 4.16 (2H, q, J=7 Hz),6.80 (1H, s), 7.05-7.45 (18H, m), 7.50-7.75 (3H, m), 7.93 (1H, s).

IR (KBr): 2974, 1603, 1489, 1473, 1394 cm⁻¹.

(iii) Production of1-(6-ethoxynaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol

1-(6-Ethoxynaphthalen-2-yl)-1-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol(0.60 g) was dissolved in acetic acid (10 ml) and 10% palladium carbon(0.2 g) was added and the mixture was stirred at 50° C. for 2 h and at60° C. for 3 h under a hydrogen atmosphere. The catalyst was filteredoff and the filtrate was concentrated to dryness. Recrystallization fromTHF-ethyl acetate gave the title compound (0.21 g) as a colorlesscrystalline powder.

¹H-NMR (CDCl₃) d: 0.81 (3H, d, J=6.8 Hz), 1.00 (3H, d, J=6.8 Hz), 1.47(3H, t, J=7 Hz), 2.60-2.80 (1H, m), 4.14 (2H, q, J=7 Hz), 6.99 (1H, s),7.09-7.15 (2H, m), 7.49-7.55 (2H, m), 7.65 (1H, d, J=8.8 Hz), 7.71 (1h,d, J=8.8 Hz), 7.91 (1H, d, J=1.8 Hz).

IR (KBr): 2976, 1633, 1604, 1504, 1473, 1392, 1260, 1219 cm⁻¹.

REFERENCE EXAMPLE 4 Production ofN-{6-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]naphthalen-2-yl}acetamide

(i) Production ofN-{6-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]naphthalen-2-yl}acetamide

1-{6-[(Diphenylmethylene)amino]naphthalen-2-yl}-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol(15.0 g) was dissolved in THF (5 ml)-methanol (5 ml) and sodium acetate(285 mg) and hydroxylamine hydrochloride (181 mg) were added. Themixture was stirred at room temperature for 20 min. 0.1N aqueous sodiumhydroxide solution was added and the mixture was extracted with ethylacetate, washed with saturated brine and dried to give a crude productof1-(6-aminonaphthalen-2-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanolas a pale-yellow oily substance. This product was dissolved indichloromethane (100 ml), and pyridine (5.3 ml) and acetic anhydride(4.1 ml) were added. The mixture Was stirred at room temperature for 40min. Saturated aqueous sodium hydrogen carbonate was added, and themixture was extracted with dichloromethane and dried. The solvent wasevaporated and the residue was recrystallized from ethyl acetate to givethe title compound (11.6 g) as pale-red crystals.

¹H-NMR (CDCl₃+CD₃OD) δ: 0.75 (3H, d, J=6.7 Hz), 0.95 (3H, d, J=6.7 Hz),2.20 (3H, s), 2.57-2.71 (1H, m), 6.87 (1H, d, J=1.4 Hz), 7.10-7.15 (6H,m), 7.32-7.54 (12H, m), 7.68-7.77 (2H, m), 7.92 (1H, s), 8.15 (1H, 9),9.60 (1H, br s).

IR (KBr): 3058, 2969, 1686, 1611, 1547, 1493, 1445, 1298, 1011, 766,747, 700 cm⁻¹.

(ii) Production ofN-{6-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]naphthalen-2-yl}acetamide

N-{6-[1-Hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]naphthalen-2-yl}acetamide(11.5 g) and pyridine hydrochloride (390 mg) were dissolved in methanol(8 ml) and the mixture was stirred at 60° C. for 2 h. After allowing tocool, the mixture was neutralized with saturated aqueous sodium hydrogencarbonate. The solvent was evaporated and the residue was collected byfiltration and washed with ethanol. The filtrate was concentrated andthe obtained residue was purified by silica gel column chromatography(eluate, dichloromethane:methanol =30:1→10:1) and recrystallized fromethyl acetate to give the title compound (5.52 g) as a pale-red powder.

¹H-NMR (CDCl₃+CD₃OD) δ: 0.79 (3H, d, J=6.8 Hz), 1.0 (3H, d, J=6.8 Hz),2.17 (3H, s), 2.63-2.76 (1H, m), 6.99 (1H, s), 7.43-7.54 (3H, m),7.65-7.74 (2H, m), 7.91 (1H, s), 8.11 (1H, s).

IR (KBr): 3248, 2971, 1669, 1609, 1586, 1557, 1495, 1391, 1296, 818cm⁻¹.

REFERENCE EXAMPLE 5 Production of1-(6,7-dimethoxynaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol

(i) Production of ethyl 2,3-dimethoxynaphthalene-6-carboxylate

Lithium diisopropylamide THF solution (2 M; 65 ml) was diluted with THF(100 ml) and cooled to −78° C. A solution of ethyl1,3-dioxan-3-propanoate (20.12 g) in THF (30 ml) was slowly addeddropwise and the mixture was stirred at −78° C. for 1 h. A solution of3,4-dimethoxybenzaldehyde (17.59 g) in THF (40 ml) was slowly addeddropwise and the mixture was stirred at −78° C. for 1 h and warmed toroom temperature. To the reaction mixture was added saturated aqueoussolution of ammonium chloride and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, dried andconcentrated. The residue was purified by silica gel columnchromatography (eluate, hexane:ethyl acetate=2:1) to give ethyl3-(3,4-dimethoxyphenyl)-2-(1,3-dioxan-2-ylmethyl)-3-hydroxypropionate(33.09 g) as an oil. This product was diluted with toluene (400 ml) andpolyphosphoric acid (54 g) was added. The mixture was stirred at 100° C.for 15 min. After cooling, water was added to the reaction mixture andthe mixture was extracted with ethyl acetate. The organic layer waswashed with saturated aqueous sodium hydrogen carbonate and saturatedbrine and dried over anhydrous magnesium sulfate the solvent wasevaporated and the residue was purified by silica gel columnchromatography (eluate, hexane:ethyl acetate=4:1) and crystallized fromethyl acetate-hexane to give the title compound (16.01 g) as a colorlesssolid.

¹H-NMR (CDCl₃) δ: 1.44 (3H, t, J=7.2 Hz), 4.01 (3H, s), 4.02 (3H, s),4.42 (2H, q, J=7.2 Hz), 7.14 (1H, s), 7.21 (1H, s), 7.70 (1H, d, J=8.5Hz), 7.94 (1H, dd, J=8.5, 1.8 Hz), 8.45 (1H, m).

IR (KBr): 2978, 1713, 1489, 1238 cm⁻¹.

(ii) Production of (6,7-dimethoxynaphthalen-2-yl)methanol

Lithium aluminum hydride (2.77 g) was added to THF (200 ml) and themixture was cooled to 0° C. Ethyl 2,3-dimethoxynaphthalene-6-carboxylate(14.30 g) was slowly added and the mixture was stirred at roomtemperature for 1 h. To the reaction mixture was added 1N hydrochloricacid and the mixture was extracted with ethyl acetate. The organic layeras dried and concentrated, and the residue was recrystallized from ethylacetate-diisopropyl ether to give the title compound (9.73 g) as acolorless solid.

¹H-NMR (CDCl₃) δ: 3.99 (3H, s), 4.00 (3H, s), 4.80 (2H, s), 7.10 (1H,s), 7.11 (1H, s), 7.33 (1H, dd, J=8.4, 1.8 Hz), 7.60-7.72 (2H, m).

IR (KBr): 3299, 1514, 1497, 1262, 1161, 856 cm⁻¹.

(iii) Production of 6,7-dimethoxy-2-formyl naphthalene

By the reaction in the same manner as in Reference Example 1-(ii) using(6,7-dimethoxynaphthalen-2-yl)methanol (9.26 g), the title compound(7.40 g) was obtained as a colorless solid.

¹H-NMR (CDCl₃) δ: 4.04 (6H, s), 7.17 (1H, s), 7.26 (1H, s), 7.76 (1H, d,J=8.4 Hz), 7.83 (1H, dd, J=8.4, 1.6 Hz), 8.19 (1H, m), 10.10 (1H, s).

IR (KBr): 1688, 1487, 1211, 1157 cm⁻¹.

(iv) Production of(6,7-dimethoxynaphthalen-2-yl)(1H-imidazol-4-yl)ketone

4-Bromo-1H-imidazol (1.95 g) was dissolved in THF (30 ml) and themixture was cooled to −78° C. A solution (1.7 M; 20 ml) oft-butyllithium in pentane was added. The mixture was stirred at 0° C.for 1.5 h and again cooled to −78° C. A solution (20 ml) of6,7-dimethoxy-2-formyl naphthalene (3.32 g) in THF was added and themixture was warmed from −78° C. to room temperature. The mixture wasstirred at room temperature for 16 h and aqueous solution of ammoniumchloride was added. The mixture was extracted with ethyl acetate and theorganic layer was dried and concentrated. The residue was purified bysilica gel column chromatography (eluate, dichloromethane:methanol=10:1)and crystallized from dichloromethane-methanol to give the titlecompound (1.31 g) as a colorless solid.

¹H-NMR (DMSO-d₆) δ: 3.93 (3H, s), 3.94 (3H, s), 7.39 (1H, s), 7.53 (1H,s), 7.80-8.03 (5H, m), 8.72 (1H, brs).

IR (KBr): 3088, 1636, 1508, 1489, 1260, 1159, 883 cm⁻¹.

(v) Production of1-(6,7-dimethoxynaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol

By the reaction in the same manner as in Reference Example 1-(iv) using(6,7-dimethoxynaphthalen-2-yl)(1H-imidazol-4-yl)ketone (0.804 g), thetitle compound (0.613 g) was obtained as a colorless solid.

¹H-NMR (CDCl₃) δ: 0.81 (3H, d, J=6.6 Hz), 1.00 (3H, d, J=6.6 Hz),2.60-2.78 (1H, m), 3.96 (3H, s), 3.97 (3H, s), 6.98 (1H, d, J=1.0 Hz),7.07 (1H, s), 7.11 (1H, s), 7.41-7.49 (2H, m), 7.61 (1H, d, J=8.4 Hz),7.89 (1H, d, J=1.4 Hz).

IR (KBr): 3322, 2965, 1510, 1254, 1163, 731 cm⁻¹.

EXAMPLE 1 Production of salt of(−)-1-(6,7-dimethoxynaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanoland (−)-8-hydroxy-7,9-dioxa-6-phenyl-8-phosphaspiro[4.5]decan-8-one

A racemate (200 mg) of1-(6,7-dimethoxynaphthalen-2-yl)-(1-H-imidazol-4-yl)-2-methyl-1-propanoland (−)-8-hydroxy-7,9-dioxa-6-phenyl-8-phosphaspiro[4.5]decan-8-one(164.4 mg) were dissolved in ethanol (4.0 ml) by heating. The mixturewas stood still at room temperature overnight, and the precipitate wascollected by filtration to give 153.7 mg of white crystals. As a resultof the HPLC analysis (Condition B), the diastereomer excess was found tobe 92% de.

To this salt (151 mg) was added ethanol (1.5 ml) and the mixture wasstood as it was for 3 days. Crystals were collected by filtration togive 130.5 mg of white crystals (yield 72.2%). As a result of the HPLCanalysis (Condition B), the diastereomer excess was found to be 99% de.

EXAMPLE 2 Production of(−)-1-(6,7-dimethoxynaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol

A racemate (1.0 g) of1-(6,7-dimethoxynaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanoland (−)-8-hydroxy-7,9-dioxa-6-phenyl-8-phosphaspiro[4.5]decan-8-one (822mg) were dissolved in ethanol (21 ml) by heating and the mixture wasstirred at room temperature for 6 h. The precipitate was collected byfiltration to give 670 mg of white crystals (yield 74%). As a result ofthe HPLC analysis (Condition B), the diastereomer excess was found to be99% de.

This salt (665 mg) was added to 25% aqueous ammonia (150 mg), water 20ml and ethyl acetate (20 ml) and the mixture was stirred at roomtemperature for 30 min, followed by partitioning. The organic layer wasconcentrated under reduced pressure to give 368 mg of a dry solid (yield74%). As a result of the HPLC analysis (Condition B), the enantiomerexcess was found to be 99% ee.

EXAMPLE 3 Production of salt of(−)-1-(6,7-dimethoxynaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanoland (R)-(−)-1,1′-binaphthyl-2,2′-diyl hydrogen phosphate

A racemate (50 mg) of1-(6,7-dimethoxynaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanoland (R)-(−)-1,1′-binaphthyl-2,2′-diyl hydrogen phosphate (53.4 mg) weredissolved in ethanol 0.9 ml and the mixture was concentrated to dryness.To the dry solid were added acetonitrile (0.3 ml) and water (0.3 ml) toallow crystallization. Thereto was further added tetrahydrofuran (0.3ml) and dissolved by heating. The mixture was stirred under roomtemperature for 1 h and the precipitate was collected by filtration togive 24.5 mg of crystals (yield 47%). As a result of the HPLC analysis(Condition B), the diastereomer excess was found to be 75% de.

EXAMPLE 4 Production of salt of(−)-1-(6,7-dimethoxynaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanoland (−)-2-hydroxy-5,5-dimethyl-4-phenyl-1,3,2-dioxaphosphorinan-2-one

A racemate (200 mg) of1-(6,7-dimethoxynaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanoland (−)-2-hydroxy-5,5-dimethyl-4-phenyl-1,3,2-dioxaphosphorinan-2-one(148 mg) were dissolved in ethanol (5 ml) and the mixture was stoodovernight at room temperature. The precipitate was collected byfiltration to give 117.6 mg of white crystals (yield 68%). Therefrom 117mg was suspended in isopropanol (1 ml) and ethanol (2 ml) and themixture was stirred under room temperature for 3 h. The crystals werecollected by filtration to give 93.0 mg of white crystals (yield 54%).As a result of the HPLC analysis (Condition B), the diastereomer excesswas found to be 97% de.

EXAMPLE 5 Production of salt of(−)-1-(1H-imidazol-4-yl)-1-(6-methoxy-2-naphthyl)-1-butanol and(−)-4-(2-chlorophenyl)-2-hydroxy-5,5-dimethyl-1,3,2-dioxaphosphorinan-2-one

A racemate (40 mg) of1-(1H-imidazol-4-yl)-1-(6-methoxy-2-naphthyl)-1-butanol and(−)-4-(2-chlorophenyl)-2-hydroxy-5,5-dimethyl-1,3,2-dioxaphosphorinan-2-one(37.3 mg) were dissolved in ethanol (0.3 ml) and tetrahydrofuran (0.2ml) and the mixture was preserved in a refrigerator overnight. The nextday, the precipitate was collected by filtration to give 4.1 mg ofcrystals (yield 11%). As a result of the HPLC analysis (Condition B),the diastereomer excess was found to be 76% de.

EXAMPLE 6 Production of salt of(−)-1-(6-ethoxy-2-naphthyl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol and(−)-4-(2,4-dichlorophenyl)-2-hydroxy-5,5-dimethyl-1,3,2-dioxaphosphorinan-2-one

A racemate (40 mg) of1-(6-ethoxy-2-naphthyl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol and(−)-4-(2,4-dichlorophenyl)-2-hydroxy-5,5-dimethyl-1,3,2-dioxaphosphorinan-2-one(40.1 mg) were dissolved in ethanol (0.4 ml) and methanol (0.4 ml) wasadded. The mixture was stood at room temperature for six days. Theretowere added ethanol (0.4 ml) and isopropanol (0.4 ml), and afterstirring, the precipitate was collected by filtration to give 26.3 mg ofcrystals (yield 66%). As a result of the HPLC analysis (Condition B),the diastereomer excess was found to be 79% de.

EXAMPLE 7 Production of salt of(+)-N-{6-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]naphthalen-2-yl}acetamideand(+)-2-hydroxy-4-(2-methoxyphenyl)-5,5-dimethyl-1,3,2-dioxaphosphorinan-2-one

A racemate (50 mg) ofN-{6-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]naphthalen-2-yl}acetamideand(+)-2-hydroxy-4-(2-methoxyphenyl)-5,5-dimethyl-1,3,2-dioxaphosphorinan-2-one(42 mg) were dissolved in ethanol (0.9 ml) with heating, and seedcrystal (>99% de) was added. The mixture was stood in a refrigeratorovernight. The precipitate was collected by filtration to give 21.7 mgof crystals (yield 47%). As a result of the HPLC analysis (Condition B),the diastereomer excess was found to be 99% de.

EXAMPLE 8 Production of(−)-1-(1H-imidazol-4-yl)-1-(6-methoxynaphthalen-2-yl)-2-methyl-1-propanol

A racemate (24 g) of1-(1H-imidazol-4-yl-1-(6-methoxynaphthalen-2-yl)-2-methyl-1-propanol wasdissolved in tetrahydrofuran (60 ml) and ethanol (630 ml) by heating. Tothis solution were added(−)-4-(2,4-dichlorophenyl)-2-hydroxy-5,5-dimethyl-1,3,2-dioxaphosphorinan-2-one(25.2 g) and ethanol (20 ml). The seed crystal (>99% de) was added, andthe mixture was stirred at room temperature overnight. The precipitatewas collected by filtration and dried to give 23.5 g of crystals. As aresult of the HPLC analysis (Condition B), the diastereomer excess wasfound to be B9% de.

The above-mentioned salt was suspended in ethanol (400 ml),tetrahydrofuran (40 ml) and methanol (10 ml) and the mixture was stirredfor overnight. The crystals obtained by filtration and drying was 20.4 g(yield 86%). As a result of the HPLC analysis (Condition B), thediastereomer excess was found to be 98% de.

The crystals (20.4 g) were suspended in ethanol (300 ml) andtetrahydrofuran (30 ml) and the mixture was stirred at room temperatureovernight. Filtration and drying gave 18.6 g of crystals (yield 91%). Asa result of the HPLC analysis (Condition B), the diastereomer excess wasfound to be 99% de.

The purified salt was stirred in water (about 300 ml) and 1N aqueoussodium hydroxide solution (32 ml) for 5 h. After decomposition, theprecipitate was collected and washed with warm water. The obtainedcrystals were 8.6 g (yield 96%). As a result of the HPLC analysis(Condition B), the enantiomer excess was found to be 98% ee.

Melting point: 179-181° C.

EXAMPLE 9 Production of salt of(−)-1-(1H-imidazol-4-yl)-1-(6-methoxynaphthalen-2-yl)-2-methyl-1-propanoland(−)-4-(2-chlorophenyl)-2-hydroxy-5,5-dimethyl-1,3,2-dioxaphosphorinan-2-one

A racemate (200 mg) of1-(1H-imidazol-4-yl-1-(6-methoxynaphthalen-2-yl)-2-methyl-1-propanol wassuspended in tetrahydrofuran (0.5 ml) and ethanol (3.5 ml) and dissolvedby heating.(−)-4-(2-Chlorophenyl)-2-hydroxy-5,5-dimethyl-1,3,2-dioxaphosphorinan-2-one(188 mg) and ethanol (1.5 ml) were added, and the mixture was stood atroom temperature overnight. The crystals were collected by filtrationand dried to give 181.9 mg (yield 94%). As a result of the HPLC analysis(Condition B), the diastereomer excess was found to be 91% de.

EXAMPLE 10 Production of salt of(−)-1-(1H-imidazol-4-yl)-1-(6-methoxynaphthalen-2-yl)-2-methyl-1-propanoland(−)-4-(4-chlorophenyl)-2-hydroxy-5,5-dimethyl-1,3,2-dioxaphosphorinan-2-one

A racemate (200 mg) of1-(1H-imidazol-4-yl-1-(6-methoxynaphthalen-2-yl)-2-methyl-1-propanol wasdissolved in acetonitrile (0.5 ml) and ethanol (2.5 ml) by heating and(−)-4-(4-chlorophenyl)-2-hydroxy-5,5-dimethyl-1,3,2-dioxaphosphorinan-2-one(188 mg) and ethanol (0.5 ml) were added. The mixture was stood at roomtemperature for 2 days. The precipitate was collected by filtration anddried to give the crystals (107.4 mg, yield 55%). As a result of theHPLC analysis (Condition B), the diastereomer excess was found to be 82%de.

EXAMPLE 11 Production of salt of(−)-1-(1H-imidazol-4-yl)-1-(6-methoxynaphthalen-2-yl)-2-methyl-1-propanoland(−)-2-hydroxy-4-(2-methoxyphenyl)-5,5-dimethyl-1,3,2-dioxaphosphorinan-2-one

A racemate (200 mg) of1-(1H-imidazol-4-yl-1-(6-methoxynaphthalen-2-yl)-2-methyl-1-propanol wassuspended in acetonitrile (0.5 ml) and ethanol (2.5 ml), and dissolvedwith heating.(−)-2-Hydroxy-4-(2-methoxyphenyl)-5,5-dimethyl-1,3,2-dioxaphosphorinan-2-one(181 mg) and ethanol (1.0 ml) were added and the mixture was stood atroom temperature overnight. Because no crystallization was observed,acetonitrile (0.3 ml) was further added, and the mixture was stood in arefrigerator overnight. The precipitate was collected by filtration anddried to give crystals (124.1 mg, yield 65%). As a result of the HPLCanalysis (Condition B), the diastereomer excess was found to be 81% de.

EXAMPLE 12 Production of salt of methyl6-[1-hydroxy-1-(1H-imidazol-4-yl)-3-methylbutyl]-2-naphthate and(R)-(+)-4-(2-chlorophenyl)-5,5-dimethyl-1,3,2-dioxaphosphorinan-2-ol2-oxide

A racemate (250 mg) of methyl6-[1-hydroxy-1-(1H-imidazol-4-yl)-3-methylbutyl]-2-naphthate and(R)-(+)-4-(2-chlorophenyl)-5,5-dimethyl-1,3,2-dioxaphosphorinan-2-ol2-oxide (204.5 mg) were dissolved in ethanol (2.5 ml) with heating. Thesolution was stood overnight at room temperature, and the precipitatewas collected by filtration to give 170.0 mg of white crystals. As aresult of the HPLC analysis (Condition D), the diastereomer excess wasfound to be 74% de.

To this salt (169 mg) was added ethanol (2.8 ml), and the mixture wasstirred overnight at room temperature. The crystals were collected byfiltration to give 110.4 mg of white crystals. As a result of the HPLCanalysis (Condition D), the diastereomer excess was found to be 95% de.

To this salt (109 mg) was added ethanol (1.5 ml), and the mixture wasstood at room temperature for 3 days. The crystals were collected byfiltration to give 87 mg of white crystals (yield 39%). As a result ofthe HPLC analysis (Condition D), the diastereomer excess was found to be99% de.

EXAMPLE 13 Production of salt of methyl6-[1-hydroxy-1-(1H-imidazol-4-yl)-3-methylbutyl]-2-naphthate and(R)-(+)-4-(2,4-dichlorophenyl)-5,5-dimethyl-1,3,2-dioxaphosphorinan-2-ol2-oxide

A racemate (50 mg) of methyl6-[1-hydroxy-1-(1H-imidazol-4-yl)-3-methylbutyl]-2-naphthate and(R)-(+)-4-(2,4-dichlorophenyl)-5,5-dimethyl-1,3,2-dioxaphosphorinan-2-ol2-oxide (45.6 mg) were dissolved in ethanol (0.5 ml) with heating. Thesolution was stood still overnight at room temperature, and precipitatewas collected by filtration to give 40.4 mg of white crystals (yield85%). As a result of the HPLC analysis (Condition D), the diastereomerexcess was found to be 60% de.

EXAMPLE 14 Production of salt of methyl6-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]-2-naphthate and(S)-(−)-4-(2-chlorophenyl)-5,5-dimethyl-1,3,2-dioxaphosphorinan-2-ol2-oxide

A racemate (67 mg) of methyl6-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]-2-naphthate and(S)-(−)-4-(2-chlorophenyl)-5,5-dimethyl-1,3,2-dioxaphosphorinan-2-ol2-oxide (57.2 mg) were dissolved in ethanol (0.9 ml). The mixture wasstood still overnight at room temperature and the precipitate wascollected by filtration to give 46.1 mg of white crystals. As a resultof the HPLC analysis (Condition C), the diastereomer excess was found tobe 71% de.

Ethanol (1.3 ml) was added to this salt (43.6 mg), and after refluxingfor 30 min, the mixture was stirred at room temperature overnight. Thecrystals were collected by filtration to give 22.5 mg of white crystals(yield 39%). As a result of the HPLC analysis (Condition C), thediastereomer excess was found to be 98% de.

EXAMPLE 15 Production of salt of6-[1-hydroxy-1-(1H-imidazol-4-yl)-3-methylbutyl]-N-methyl-2-naphthamideand (R)-(+)-4-(2-chlorophenyl)-5,5-dimethyl-1,3,2-dioxaphosphorinan-2-ol2-oxide

A racemate (50 mg) of6-[1-hydroxy-1-(1H-imidazol-4-yl)-3-methylbutyl]-N-methyl-2-naphthamideand (R)-(+)-4-(2-chlorophenyl)-5,5-dimethyl-1,3,2-dioxaphosphorinan-2-ol2-oxide (41.0 mg) were dissolved in acetonitrile (0.3 ml) and ethanol(0.3 ml). The mixture was stood still overnight at room temperature andthe precipitate was collected by filtration to give 34 mg of whitecrystals. As a result of the HPLC analysis (Condition D), thediastereomer excess was found to be 81% de. 1-Propanol (1.0 ml) wasadded to this salt (31 mg) and dissolved by heating. The solution wasstood at room temperature overnight. The crystals were collected byfiltration to give 15.6 mg of white crystals (yield 38%). As a result ofthe HPLC analysis (Condition D), the diastereomer excess was found to be99% de.

EXAMPLE 16 Production of salt of6-[1-hydroxy-1-(1H-imidazol-4-yl)-3-methylbutyl]-N-methyl-2- and(S)-(−)-4-(2,4-dichlorophenyl)-5,5-dimethyl-1,3,2-dioxaphosphorinan-2-ol2-oxide

A racemate (50 mg) of6-[1-hydroxy-1-(1H-imidazol-4-yl)-3-methylbutyl]-N-methyl-2-naphthamideand(S)-(−)-4-(2,4-dichlorophenyl)-5,5-dimethyl-1,3,2-dioxaphosphorinan-2-ol2-oxide (46.1 mg) were dissolved in acetonitrile (0.3 ml) and ethanol(0.3 ml). The mixture was stood still overnight at room temperature andthe precipitate was collected by filtration to give 36.6 mg of whitecrystals (yield 76%). As a result of the HPLC analysis (Condition D),the diastereomer excess was found to be 70% de.

EXAMPLE 17 Production of salt of6-[1-hydroxy-1-(1H-imidazol-4-yl)propyl]-N-methyl-2-naphthamide and(R)-(+)-4-(2-chlorophenyl)-5,5-dimethyl-1,3,2-dioxaphosphorinan-2-ol2-oxide

A racemate (50 mg) of6-[1-hydroxy-1-(1H-imidazol-4-yl)propyl]-N-methyl-2-naphthamide and(R)-(+)-4-(2-chlorophenyl)-5,5-dimethyl-1,3,2-dioxaphosphorinan-2-ol2-oxide (44.7 mg) were dissolved in dimethoxyethane (0.5 ml) andisopropyl alcohol (0.1 ml). The mixture was stood still overnight atroom temperature and the precipitate was collected by filtration to give45.7 mg of white crystals. As a result of the HPLC analysis (ConditionD), the diastereomer excess was found to be 58% de.

Tetrahydrofuran (1.6 ml) and isopropanol (0.2 ml) were added to thissalt (42 mg) and the mixture was stood overnight at room temperature.The crystals were collected by filtration to give 28.8 mg of whitecrystals (yield 67%). As a result of the HPLC analysis (Condition D),the diastereomer excess was found to be 79% de.

EXAMPLE 18 Production of salt of6-[1-hydroxy-1-(1H-imidazol-4-yl)-propyl]-N-methyl-2-naphthamide and(R)-(+)-4-(2-chlorophenyl)-5,5-dimethyl-1,3,2-dioxaphosphorinan-2-ol2-oxide

A racemate (50 mg) of6-[1-hydroxy-1-(1H-imidazol-4-yl)-propyl]-N-methyl-2-naphthamide and(R)-(+)-4-(2-chlorophenyl)-5,5-dimethyl-1,3,2-dioxaphosphorinan-2-ol2-oxide (44.7 mg) were dissolved in dimethoxyethane (0.8 ml) andisopropyl alcohol (0.15 ml). The mixture was stirred at room temperatureovernight, and the precipitate was collected by filtration to give 75.5mg of white crystals. As a result of the HPLC analysis (Condition D),the diastereomer excess was found to be 10% de.

Tetrahydrofuran (1.0 ml) and isopropanol (1.0 ml) were added to thissalt (74 mg) and the mixture was stirred under room temperature for 6 h.The crystals were collected by filtration to give 27.5 mg of whitecrystals. As a result of the HPLC analysis (Condition D), thediastereomer excess was found to be 70% de.

Tetrahydrofuran (1.0 ml) and isopropanol (0.5 ml) were added to thissalt (26.5 mg) and the mixture was stirred under room temperatureovernight. The crystals were collected by filtration to give 12.8 mg ofwhite crystals (yield 28%). As a result of the HPLC analysis (ConditionD), the diastereomer excess was found to be 99% de.

mp; 185-186° C.

EXAMPLE 19 Production of salt of6-[1-hydroxy-1-(1H-imidazol-4-yl)propyl]-N-methyl-2-naphthamide and(R)-(+)-4-(2,4-dichlorophenyl)-5,5-dimethyl-1,3,2-dioxaphosphorinan-2-ol2-oxide

A racemate (50 mg) of6-[1-hydroxy-1-(1H-imidazol-4-yl)propyl]-N-methyl-2-naphthamide and(R)-(+)-4-(2,4-dichlorophenyl)-5,5-dimethyl-1,3,2-dioxaphosphorinan-2-ol2-oxide (50.3 mg) were dissolved in dimethoxyethane (0.5 ml) andmethanol (0.1 ml). The mixture was stood still overnight at roomtemperature and the precipitate was collected by filtration to give 23.7mg of white crystals (yield 47%). As a result of the HPLC analysis(Condition D), the diastereomer excess was found to be 69% de.

EXAMPLE 20 Production of salt of6-[1-hydroxy-1-(1H-imidazol-4-yl)propyl]-N-methyl-2-naphthamide and(R)-(+)-4-(2-methoxyphenyl)-5,5-dimethyl-1,3,2-dioxaphosphorinan-2-ol2-oxide

A racemate (50 mg) of6-[1-hydroxy-1-(1H-imidazol-4-yl)propyl]-N-methyl-2-naphthamide and(R)-(+)-4-(2-methoxyphenyl)-5,5-dimethyl-1,3,2-dioxaphosphorinan-2-ol2-oxide (44.0 mg) were dissolved in dimethoxyethane (0.5 ml) andmethanol (0.1 ml). The mixture was stood still overnight at roomtemperature and the precipitate was collected by filtration to give 32.1mg of white crystals (yield 68%). As a result of the HPLC analysis(Condition D), the diastereomer excess was found to be 56% de.

EXAMPLE 21 (1) Production of ethyl 1-benzoylcyclopentanecarboxylate

Diiodobutane (17.1 g, 55 mmol), sodium carbonate (35 g, 330 mmol),ethylbenzoylacetate (10.6 g, 55 mmol) and dimethylformamide (170 ml)were mixed and the mixture was stirred at 55 to 60° C. overnight. Themixture after completion of reaction was poured into ice water and themixture was extracted twice with ethyl acetate (100 ml). The extract wasdried over sodium sulfate, and after concentration, purified by silicagel column chromatography (hexane:ethyl acetate=9:1) to give the titlecompound (7.9 g, 58%) as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.97 (3H, t, J=7.1 Hz), 1.66-1.78 (4H, m),2.28-2.40 (4H, m), 4.05 (2H, q, J=7.1 Hz), 7.86 (2H, d, J=7.3 Hz),7.39-7.51 (3H, m).

IR (neat) ν cm⁻¹: 2959, 1734, 1685.

(2) Production of ethyl 1-(1-hydroxyphenylmethyl)cyclopentanecarboxylate

(S)-tBuBisP*-RuBr₂ (5 mg) was placed in a reactor, and after deaerationand substitution with argon, a mixture of ethyl1-benzoylcyclopentanecarboxylate (246 mg, 1 mmol) and methanol(deaeration, 5 ml) was added. Under room temperature and hydrogenpressure (6 kg/cm²), the mixture was stirred overnight and the mixtureafter completion of reaction was concentrated to dryness. This wasconcentrated and purified by silica gel column chromatography(hexane:ethyl acetate=3:1) to give a colorless oil (150 mg, 61%). Theenantiomer excess was measured by high performance liquid chromatography(Condition (B)) and found to be 95.0% ee.

¹H-NMR (400 MHz, CDCl₃) δ: 1.20 (3H, t, J=7.1 Hz), 1.56-2.17 (8H, m),3.49 (1H, d, J=6.3 Hz), 4.11-4.14 (2H, m), 4.80 (1H, d, J=6.3 Hz),7.25-7.30 (5H, m).

IR (NaCl) ν cm⁻¹: 3496, 2957, 1717.

(3) Production of1-(1-hydroxy-1-phenylmethyl)-1-hydroxymethylcyclopentane

Lithium aluminum hydride (1.05 g, 27.6 mmol) was suspended in ether (80ml) and the mixture was cooled to −20° C. to −30° C. Thereto was addeddropwise a solution of ethyl1-(1-hydroxyphenylmethyl)cyclopentanecarboxylate (14.118.4 mmol) inether (10 ml) while maintaining the solution at not higher than −20° C.The mixture was stirred at −20° C. for 1 h and at room temperature for 3h, cooled to −20° C. and 10% NaHSO₄ aqueous solution (40 ml) was addeddropwise. The mixture was stirred at 0° C. for 30 min and an insolublematerial was removed by decantation. This was washed twice with ether(100 ml), and the organic layer was combined, washed with water anddried over anhydrous sodium sulfate. This was concentrated to dryness togive a colorless oil (3.12 g).

¹H-NMR (400 MHz, CDCl₃) δ: 1.49-1.80 (8H, m), 2.97 (1H, brs), 3.20 (1H,brs), 3.37 (1H, dd, J=1.8 and 10.9 Hz), 3.63 (1H, d, J=10.9 Hz), 4.71(1H, s), 7.26-7.40 (5H, m).

(4) Production of8-chloro-7,9-dioxa-6-phenyl-8-phosphospiro[4.5]decan-8-one

1-(1-Hydroxyphenylmethyl)-1-hydroxymethylcyclopentane (3.0 g, 14.5 mmol)was diluted with dichloromethane (16 ml), and under refluxing, asolution of phosphorus oxychloride (2.38 g, 15.5 mmol) indichloromethane (12 ml) was added dropwise over 30 min. After thedropwise addition, the mixture was refluxed for 5 h. The mixture aftercompletion of the reaction was concentrated. Ether (dry, 5 ml) wasadded, and the mixture was stirred under ice-cooling for 30 min. Thiswas filtrated to give white crystals (3.0 g). The mother liquor wasconcentrated to dryness, and ether (5 ml) was added. The mixture wasstirred under ice-cooling for 30 min. This was filtrated to give secondcrystals (0.28 g), total yield 79%.

(5) Production of8-hydroxy-7,9-dioxa-6-phenyl-8-phosphospiro[4.5]decan-8-one

Sodium hydroxide (0.67 g) was dissolved in water (8 ml) and the solutionwas heated to 95 to 100° C., and8-chloro-7,9-dioxa-6-phenyl-8-phosphospiro[4.5]decan-8-one (3.2 g, 11.2mmol) was added as a powder over 30 min, and the mixture was stirred atthe same temperature for 20 min. The reaction mixture was allowed tocool to 60° C. and concentrated hydrochloric acid (3 ml) was added. Themixture was cooled to 13° C. to 15° C. Precipitated white crystals werecollected by filtration, washed successively with water (2 ml) and ether(2 ml) and vacuum dried to give white crystals (2.6 g, 87%). Theenantiomer excess of this product was measured by high performanceliquid chromatography and found to be 91% ee.

This was dissolved in ethanol with heating and recrystallized to givewhite crystals (1.5 g, yield 58%). The enantiomer excess of this productwas measured by high performance liquid chromatography (Condition (A))and found to be not less than 99% ee.

¹H-NMR (400 MHz, CDCl₃) δ: 0.76-1.74 (8H, m), 3.93 (1H, dd, J=1.11 and24.4 Hz), 4.20 (1H, d, J=11.1 Hz), 5.43 (1H, s), 7.33-7.41 (5H, m).

IR (KBr) ν cm⁻¹: 2292, 1734, 1205.

[α]²⁴ _(D)=−60.8° (c=1.0, methanol).

EXAMPLE 22 (1) Production of ethyl1-(1-hydroxy-1-phenylmethyl)cyclopentanecarboxylate

To N,N-dimethylformamide (400 ml) were added ethyl benzoylacetate (25.1g, 0.13 mol), 1,4-diiodobutane (40.47 g) (0.13 g) and anhydrous sodiumcarbonate (82.7 g, 0.78 mol) and the mixture was stirred at 60° C. for15.5 h. The reaction mixture was poured into 1 L of water and themixture was extracted with ethyl acetate. The extract was washed withsaturated brine, dehydrated over anhydrous sodium sulfate andconcentrated. A red residual solution (33.5 g) was purified by silicagel column chromatography (ethyl acetate/hexane=1/4) to give the titlecompound (24.67 g) as a colorless oil (yield 77%).

¹H-NMR (90 MHz, CDCl₃) δ: 0.97 (3H, t, J=7.0 Hz), 1.64-1.79 (4H, m),2.26-2.44 (4H, m), 4.05 (2H, q, J=7.0 Hz), 7.29-7.52 (3H, m), 7.80-7.91(2H, m).

(2) Production of 1-(hydroxyphenylmethyl)-1-hydroxymethylcyclopentane

Under a nitrogen stream, lithium aluminum hydride (0.38 g, 0.01 mol) wassuspended in dehydrating ether (8 ml) and ethyl1-(1-hydroxy-1-phenylmethyl)cyclopentanecarboxylate (2.46 g, 0.01 mol)as 8 ml of a dehydrating ether solution was added dropwise over 30 minwhile stirring the mixture at room temperature. After the completion ofdropwise addition, the mixture was stirred for 30 min while gentlyrefluxing, then 10% aqueous sodium hydrogen carbonate (1 ml) was slowlyadded dropwise under ice-cooling. Then 20% aqueous sodium hydroxide (2ml) was added dropwise and the ether layer was taken by decantation. Theresidue was washed twice with ether (10 ml). The ether layer wascombined and the mixture was dehydrated over anhydrous magnesium sulfateand concentrated. The residual solution (2.01 g) was purified by silicagel column chromatography (ethyl acetate/hexane=2/3) to give the titlecompound (1.8 g) as a colorless oil (yield 87%).

¹H-NMR (400 MHz, CDCl₃) δ: 1.06-1.11 (1H, m), 1.50-1.63 (5H, m),1.70-1.81 (2H, m), 2.95 (1H, t), 3.16 (1H, d), 3.38 (1H, dd, J=5.3 Hz,11.0 Hz), 3.64 (1H, dd, J=3.4 and 11.0 Hz), 4.71 (1H, d, J=3.4 Hz),7.26-7.40 (5H, m).

(3) Production of8-chloro-7,9-dioxa-6-phenyl-8-phosphaspiro[4.5]decan-8-one

1-(Hydroxyphenylmethyl)-1-hydroxymethylcyclopentane (23.3 g, 0.113 mol)was dissolved in dichloromethane (90 ml), and the mixture was heatedunder reflux with stirring. Phosphorus oxychloride (18.2 g, 0.119 mol)was dissolved in dichloromethane (45 ml) and added dropwise to themixture over 45 min. The mixture was stirred at same temperature for 3 hand concentrated under reduced pressure. Diisopropyl ether (100 ml) wasadded to the residue and the mixture was stirred. The precipitatedcrystals were collected by filtration, and washed with diisopropyl etherto give the title compound (22.78 g), melting point: 130-132° C. aswhite crystals (yield 70%).

¹H-NMR (400 MHz, CDCl₃); 0.98-1.04 (1H, m), 1.25-1.31 (2H, m), 1.48-1.55(2H, m), 1.63-1.70 (1H, m), 1.85-1.94 (2H, m), 4.15 (1H, m), 4.40 (1H,d, J 11.2 Hz), 5.51 (1H, m), 7.28-7.40 (5H, m).

(4) Production of8-hydroxy-7,9-dioxa-6-phenyl-8-phosphaspiro[4.5]decan-8-one

Sodium hydroxide (9.2 g, 0.23 mol) was dissolved in water (92 ml) andthe mixture was stirred at 98 to 103° C. with heating, during which8-chloro-7,9-dioxa-6-phenyl-8-phosphaspiro[4.5]decan-8-one (21.56 g,0.0752 mol) obtained in 3-1) was pulverized and added in small portionsover 10 min, and the pale-orange solution was further stirred for 25min. The reaction mixture was allowed to cool to 45°C. and concentratedhydrochloric acid (19.5 ml) was added to make the solution acidic. Water(40 ml) was added and the mixture was cooled to 20° C. The fine crystalswere collected by filtration and washed with water and then ether. Thecrystals were dried under reduced pressure at 50° C. to give the titlecompound (16.56 g, yield 81%) as white crystals, melting point: 173 to174° C.

¹H-NMR (400 MHz, CDCl₃+DMSO-d₆); 0.92-0.98 (1H, m), 1.14-1.25 (2H, m),1.40-1.48 (2H, m), 1.50-1.61 (1H, m), 1.85-1.88 (2H, m), 3.94 (1H, dd,J=11.0 Hz and 24.4 Hz), 4.30 (1H, d, J=11.0 Hz), 5.10 (1H, br s), 5.43(1H, s), 7.35-7.38 (5H, m).

(5) Production of(−)-8-hydroxy-7,9-dioxa-6-phenyl-8-phosphaspiro[4.5]decan-8-one

(−)-8-hydroxy-7,9-dioxa-6-phenyl-8-phosphaspiro[4.5]decan-8-one

A racemate (16.3 g, 0.06 mol) of8-hydroxy-7,9-dioxa-6-phenyl-8-phosphaspiro[4.5]decan-8-one andD-(−)-p-hydroxyphenyl glycine (10.16 g, 0.06 mol) were added to ethanol(250 ml) and water (130 ml). The mixture was refluxed for 10 min, duringwhich crystals were mostly dissolved, and the crystals were allowed toprecipitate again. The mixture was stirred under room temperature for 1h and stood in a refrigerator overnight.

The precipitated crystals of a salt of(−)-8-hydroxy-7,9-dioxa-6-phenyl-8-phosphaspiro[4.5]decan-8-one andD-(−)-p-hydroxyphenyl glycine were collected by filtration and washedwith ethanol to give 11.82 g thereof.

The crystals were refluxed in ethanol (250 ml) and water (150 ml) for 10min and stood overnight in a refrigerator. The precipitated crystalswere collected by filtration to give white crystals (9.73 g, meltingpoint: from 225° C. to 227° C. (dec.)). [α]_(D) ²⁰−101.2° (c=0.5,methanol) The crystals were suspended in 60 ml of water and 36%hydrochloric acid (12 ml) was added. The mixture was stirred at roomtemperature for 4 h to allow double decomposition. This was filtrated,washed with water and the obtained crystals (6.06 g) were recrystallizedfrom 130 ml of ethanol to give the title compound as white crystals(5.04 g, yield 62%, m.p. 163-164° C.). As a result of the HPLC analysis(Condition C), the enantiomer excess was found to be not less than 99%ee.

[α]_(D) ²⁰=−60.6° (c=0.5, methanol).

Elemental analysis for C₁₃H₁₇O₄P₁.

Calculated C, 58.21%; H, 6.39%;

Found C, 58.14%; H, 6.25%.

(6) Production of(+)-8-hydroxy-7,9-dioxa-6-phenyl-8-phosphaspiro[4.5]decan-8-one

The crystals of a salt of(−)-8-hydroxy-7,9-dioxa-6-phenyl-8-phosphaspiro[4.5]decan-8-one andD-(−)-p-hydroxyphenyl glycine were collected by filtration. The filtratewas concentrated to dryness and dissolved again in ethanol (100 ml) andwater (50 ml). After standing at room temperature for one day, theprecipitated crystals were collected by filtration (4.2 g). Ethanol wasevaporated from the filtrate under reduced pressure, and 36%hydrochloric acid (15 ml) was added. The mixture was stirred at roomtemperature for 4 h to allow double decomposition. This was filtratedand washed with water to give 5.79 g of crystals (yield 70.8%). [α]_(D)²⁰=+49.0° (c=0.5, methanol) The crystals were recrystallized twice fromethanol to give the title compound as white crystals (3.34 g, yield 41%,m.p. 160-161° C.). [α]_(D) ²⁰=+59.4° (c=0.5, methanol). As a result ofthe HPLC analysis (Condition (C)), the enantiomer excess was found to benot less than 99% ee.

Elemental analysis for C₁₃H₁₇O₄P₁.

Calculated C, 58.21%; H, 6.39%;

Found C, 58.06%; H, 6.25%.

EXAMPLE 23 (3) Synthesis of ethyl 2,2-dimethyl(2-chlorobenzoyl)acetate

2-Chlorobenzoyl chloride (17.5 g, 0.1 mol) and ethyl2-bromo-2,2-dimethylacetate (19.5 g, 0.1 mol) were diluted with ether(200 ml) and added dropwise into a 300 ml four-necked flask containing azinc powder (13.0 g, 0.2 mol). After adding dropwise about 30 ml, themixture was heated and the remaining solution was added dropwise over 2h under reflux. After the completion of the dropwise addition, themixture was refluxed for 4 h and allowed to cool, and 1N-hydrochloricacid (100 ml) was added dropwise. After partitioning, the aqueous layerwas extracted with ether (100 ml), and the organic layer was combined.The mixture was dried over sodium sulfate and concentrated. Theconcentrated dry solid was purified by silica gel column chromatography(silica gel 1 kg, hexane:ethyl acetate=9:1) to give the title compound(13.8 g, 54%) as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) (: 1.20 (3H, t, J=7.1 Hz), 1.52 (6H, s), 4.14(2H, q, J=7.1 Hz), 7.26-7.42 (4H, m).

(2) Production of ethyl3-(2-chlorophenyl)-3-hydroxy-2,2-dimethylpropionate

tBuBisP*-RuBr₂ (5 mg) was placed in a pressurized hydrogenation reactorequipped with a stirrer chip, and after deaeration, substituted withargon. Thereto was poured a mixture of deaerated ethyl2,2-dimethyl(2-chlorobenzoyl)acetate (515 mg) (2.0 mmol), methanol (4ml) and water (0.4 ml). The mixture was stirred under a hydrogenpressure (6 atm) at 70° C. for 24 h. According to the high performanceliquid chromatography analysis of the mixture after completion of thereaction, the yield was 97% and enantioselectivity was 90% ee. After theanalysis, the reaction mixture was concentrated to dryness and purifiedby column chromatography (hexane:ethyl acetate=3:1, silica gel: 50 g) togive the title compound (420 mg, 81.8%) as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.19 (6H, s), 1.29 (3H, t, J=7.1 Hz), 3.51(1H, d, J=4.4 Hz), 4.21 (2H, q, J=7.1 Hz), 5.51 (1H, d, J=4.4 Hz),7.19-7.54 (4H, m).

IR (KBr) ν cm⁻¹: 3494, 2983, 1714.

[α]²⁴ _(D)=−30.4° (c-1.0, chloroform).

(3) Production of 1-(2-chlorophenyl)-2,2-dimethyl-1,3-propanediol

Lithium aluminum hydride (0.5 g, 11.7 mmol) was suspended in ether (50ml) and cooled to −20° C. to −30° C. Thereto was added dropwise asolution of ethyl 2,2-dimethyl-3-hydroxy(2-chlorobenzoyl)acetate (2 g,7.8 mmol) in ether (10 ml) while maintaining at not higher than −20° C.The mixture was stirred at −20° C. for 1 h and at 0° C. for 3 h, cooledto −20° C. and 10%—NaHSO₄ aqueous solution (20 ml) was added dropwise.The mixture was stirred at room temperature for 30 min, and an insolublematerial was removed by decantation. This was washed twice with ether(100 ml) and the organic layer was combined. The mixture was washed withwater, dried over anhydrous sodium sulfate, and concentrated to drynessto give the title compound (1.3 g, 78%) as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.92 (3H, s), 0.95 (3H, s), 2.63 (1H, brs),3.11 (1H, brs), 3.60 (1H, dd, J=10.8 and 13.6 Hz), 3.64 (1H, dd, J=10.8and 13.6 Hz), 5.31 (1H, s), 7.19-7.62 (4H, m).

(4) Production of4-(2-chlorophenyl)-2-chloro-5,5-dimethyl-1,3,2-dioxaphosphorinan 2-oxide

1-(2-Chlorophenyl)-2,2-dimethyl-1,3-propanediol (1.0 g, 4.66 mmol) wasdiluted with dichloromethane (5 ml) and, under reflux, a solution ofphosphorus oxychloride (0.65 g, mmol) in dichloromethane (3 ml) wasadded dropwise over 40 min. After the dropwise addition, the mixture wasrefluxed for 6 h. The mixture after completion of the reaction wasconcentrated, and after addition of ether (dry, 5 ml), concentratedagain to dryness to give the title compound (1.23 g, 90%) as colorlesscrude crystals.

(5) Production of4-(2-chlorophenyl)-2-hydroxy-5,5-dimethyl-1,3,2-dioxaphosphorinan2-oxide

Sodium hydroxide (0.25 g) was dissolved in water (3 ml) and the solutionwas heated to 95 to 100° C.4-(2-Chlorophenyl)-2-chloro-5,5-dimethyl-1,3,2-dioxaphosphorinan 2-oxide(1.23 g, 4.18 mmol) was added as a powder over 30 min and the mixturewas stirred at the same temperature for 1 h. The reaction mixture wasallowed to cool to 60° C. and concentrated hydrochloric acid (1 ml) wasadded. The mixture was cooled to 13 to 15° C. and the precipitated whitecrystals were collected by filtration, washed successively with water (2ml) and ether (2 ml), and dried in vacuo to give white crystals (1.00 g,88.9%). The enantiomer excess of this product was measured by highperformance liquid chromatography (Condition (D)) and found to be 85.6%ee. The obtained crystals (730 mg) were dissolved in 50% aqueous ethanolsolution (3 ml) with heating and stood at room temperature. Theprecipitated crystals were collected by filtration to give the titlecompound (340 mg, 98.7% ee, yield: 50%) as white crystals. The motherliquor was concentrated to dryness and again recrystallized to recoverthe title compound from the mother liquor as white crystals (200 mg,96.5% ee., yield: 26%).

¹H-NMR (400 MHz, CDCl₃) δ: 0.84 (3H, s), 1.11 (3H, s), 3.90 (1H, q,J=11.0 Hz), 4.40 (1H, q, J=11.0 Hz), 5.88 (1H, s), 7.25-7.53 (5H, m).

EXAMPLE 24 (1) Production of ethyl 1-benzoylcyclopropanecarboxylate

To 1370 ml of acetonitrile were added ethyl benzoylacetate (49.9 g, 0.26mol), 1,2-dibromomethane (48.8 g, 0.26 g) and anhydrous potassiumcarbonate (143.6 g, 1.04 mol) and the mixture was stirred under refluxfor 18 h. After cooling, the reaction mixture was filtrated andconcentrated. The residual solution (56.3 g) was purified by silica gelcolumn chromatography (ethyl acetate/hexane=1/5) to give the titlecompound (38.7 g) as a colorless oil (yield 68%).

¹H-NMR (90 MHz, CDCl₃) δ: 0.95 (3H, t, J=7.1 Hz), 1.51-1.56 (1H, m),1.57-1.64 (3H, m), 4.04 (2H, q, J=7.1 Hz), 7.43-7.46 (2H, m), 7.53-7.57(1H, m), 7.89-7.91 (2H, m).

(2) Production of1-(1-hydroxy-1-phenylmethyl)-1-hydroxymethylcyclopropane

Under a nitrogen stream, lithium aluminum hydride (4.55 g, 0.12 mol) wassuspended in dehydrated ether (120 ml) and a solution (50 ml) of ethyl1-benzoylcyclopropanecarboxylate (21.83 g, 0.1 mol) in dehydrated etherwas added dropwise over 50 min while stirring under ice-cooling. Themixture was stirred at room temperature for 1.5 h, and 10% aqueoussodium hydrogen carbonate (15 ml) was slowly added dropwise underice-cooling. Then 20% aqueous sodium hydroxide (30 ml) was addeddropwise, and the mixture was stirred for 30 min. The ether layer wasseparated by decantation and the residue was washed twice with 30 ml ofether. The ether layer was combined, washed with saturated brine,dehydrated over anhydrous magnesium sulfate and concentrated. Theresidual solution (16.9 g) was purified by silica gel columnchromatography (chloroform/methanol=20/1) to give the title compound(14.51 g) as a colorless oil (yield 81%).

¹H-NMR (400 MHz, CDCl₃) δ: 0.42-0.47 (1H, m), 0.61-0.71 (3H, m), 2.78(1H, t, J=4.9 Hz), 3.17 (1H, dd, J=4.9 Hz and 11.5 Hz), 3.59 (1H, d,J=4.6 Hz), 3.74 (1H, dd, J=4.6 Hz and 11.5 Hz), 4.46 (1H, d, J=4.4 Hz),7.26-7.39 (5H, m).

(3) Production of6-chloro-5,7-dioxa-4-phenyl-6-phosphaspiro[2.5]octane-6-one

1-(1-Hydroxy-1-phenylmethyl)-1-hydroxymethylcyclopropane (3.2 g, 0.018mol) and triethylamine (4.01 g, 0.04 mol) were dissolved indichloromethane (30 ml), and the mixture was stirred at 5 to 8° C.Phosphorus oxychloride (2.89 g, 0.019 mol) was dissolved indichloromethane (10 ml) and the solution was added dropwise underice-cooling over 40 min. The mixture was stirred at same temperature for2 h, cooled and washed with water (30 ml). The aqueous layer wasextracted with dichloromethane (15 ml), and the organic layer wascombined and washed with saturated brine. The mixture was dehydratedover anhydrous magnesium sulfate and concentrated to give 4.48 g of anoil. This was purified by silica gel column chromatography (ethylacetate/hexane=1/1) and washed with isopropyl ether to give the titlecompound as white crystals (0.47 g, yield 10%, m.p. 81-83° C.).

¹H-NMR (400 MHz, CDCl₃); 0.35-0.40 (1H, m), 0.54-0.59 (1H, m), 0.66-0.72(2H, m), 3.71 (1H, dd, J=11.7 Hz, 29.3 Hz), 4.96 (1H, m), 5.89 (1H, m),7.27-7.41 (5H, m).

(4) Production of6-hydroxy-5,7-dioxa-4-phenyl-6-phosphaspiro[2.5]octane-6-one

Sodium hydroxide (0.18 g, 4.5 mmol) was dissolved in water (2 ml), and6-chloro-5,7-dioxa-4-phenyl-6-phosphaspiro[2.5]octane-6-one (0.4 g, 1.55mmol) was added by small portions while stirring the mixture withheating at 85-88° C. on an oil bath. The addition was completed in 5min, and the mixture was further stirred for 20 min after raising thebath temperature to 90° C. The reaction mixture was allowed to cool andconcentrated hydrochloric acid (0.6 ml) was added to make the mixtureacidic. The mixture was stirred under ice-cooling for 1.5 h and theprecipitated crystals were collected by filtration, and washed withwater and then ether to give the title compound as white crystals (0.13g, yield 35%, m.p. 122-123° C.).

¹H-NMR (400 MHz, CDCl₃+DMSO-d₆); 0.23-0.28 (1H, m), 0.41-0.46 (1H, m),0.56-0.59 (2H, m), 3.53 (1H, dd, J=11.5 Hz and 23.0 Hz), 4.82 (1H, dd,J=11.5 Hz), 5.27 (1H, s), 7.30-7.63 (5H, m).

EXAMPLE 25 6-hydroxy-5,7-dioxa-4-phenyl-6-phosphaspiro[2.5]octane-6-one(consistent synthesis from1-(1-hydroxy-1-phenylmethyl)-1-hydroxymethylcyclopropane)

1-(1-Hydroxy-1-phenylmethyl)-1-hydroxymethylcyclopropane (10.0 g, 0.0561mol) was dissolved in dichloromethane (90 ml) and triethylamine (15.9 g,0.157 mol) was added thereto. A solution of phosphorus oxychloride (8.7g, 0.0567 mol) in dichloromethane (30 ml) was added dropwise over 65 minwhile stirring the mixture under ice-cooling (5 to 8° C.). The mixturewas stirred under ice-cooling for 2 h, washed twice with water (50 ml),dried over anhydrous magnesium sulfate and concentrated. The crudeintermediate chloride compound (15.08 g) was obtained as a dark brownoil.

Sodium hydroxide (6.8 g) was dissolved in water (70 ml), and theabove-mentioned crude product (15.08 g) was added by small portionswhile stirring the mixture at an outer temperature of 83 to 87° C. Theaddition was completed in 20 min, and the mixture was heated to 90 to93° C. and stirred for 30 min. The oil bath was removed, and the mixturewas stirred for a while and diethyl ether (40 ml) was added. Then,concentrated hydrochloric acid (17 ml) was added to make the mixtureacidic. The mixture was stirred under ice-cooling for 0.5 h and thecrystals were collected by filtration, and washed successively withwater and ether to give the title compound as colorless crystals (5.65g, yield 41.9%, m.p. 120-122° C.).

EXAMPLE 26 Optical resolution of(±)-6-hydroxy-5,7-dioxa-4-phenyl-6-phosphaspiro[2.5]octane-6-one

6-Hydroxy-5,7-dioxa-4-phenyl-6-phosphaspiro[2.5]octane-6-one (racemate,13.1 g, 54.5 mmol) and (+)-cis-N-benzyl-2-(hydroxymethyl)cyclohexylamine(11.96 g, 54.6 mmol) were dissolved in ethanol (100 ml) with heating.Thereto was added ethyl acetate (150 ml) under heating and the mixturewas stood at room temperature overnight. The precipitated crystals werecollected by filtration to give a salt (9.45 g) of the (−) compound. Thecrystals were recrystallized twice from ethanol to give 6.47 g ofcrystals (m.p. 209-211° C.). [α]_(D) ²⁰=−30.0° (c=0.5, MeOH).

This was suspended in water (25 ml) and 36% hydrochloric acid (7 ml) wasadded. The mixture was stirred at room temperature for 2 h to allowdecomposition. The crystals were collected by filtration, and washedwith water to give 3.32 g of colorless crystals of (−)-compound (yield50.7%, m.p. 136-137° C.). [α]_(D) ²⁰=−47.6° (c=0.5, MeOH) As a result ofthe HPLC analysis (Condition A), the enantiomer excess was found tobe >99.9% ee.

The filtrate after collecting the salt of (−)-compound was decomposed by36% hydrochloric acid to recover 7.93 g (33.0 mmol) of crystalscontaining a large amount of (+)-compound.

Thereto was added (−)-cis-N-benzyl-2-(hydroxymethyl)cyclohexylamine(7.24 g, 33.0 mmol) and dissolved in ethanol (70 ml) with heating. Themixture was stirred at room temperature for 2 h, and under ice-coolingfor 2 h and filtrated. This was recrystallized from ethanol (60 ml) togive crystals (7.02 g, m.p. 210-211° C.). [α]_(D) ²⁰=+33.0° (c=0.5,MeOH) This was suspended in water (30 ml) and 36% hydrochloric acid (7.6ml) was added for decomposition. The crystals were collected byfiltration, washed with water and recrystallized from ethanol (90 ml) togive 2.58 g of (+)-compound as colorless crystals (m.p. 131-133° C.,yield 39.4%). [α]_(D) ²⁰=+47.8° (c=0.5, MeOH). As a result of the HPLCanalysis (Condition A), the enantiomer excess was found to be >99.9% ee.

EXAMPLE 27 (1) Production of ethyl1-(1-hydroxy(2-chlorophenyl)methyl)cyclopentanecarboxylate

^(t)BuBisP*RuBr₂ (28 mg) was placed in a reactor and deaerated andsubstituted with argon. A mixture of deaerated methanol/water (10/1) (33ml) and ethyl 1-(2-chlorobenzoyl)cyclopentanecarboxylate (3.2 g, 11.4mmol) was added. Under a hydrogen pressure (6 atm), the mixture wasstirred at 70° C. for 7 h and concentrated to dryness. This wasdissolved in ethyl acetate, dried over anhydrous sodium sulfate andpurified by silica gel column chromatography to give the title compound(2.59 g, yield; 80.9%) as a colorless oil. The enantiomer excess of thisproduct was measured by high performance liquid chromatography(Condition F) and found to be 90% ee.

¹H-NMR (400 MHz, CDCl₃) δ: 1.25 (3H, t, J=7.1 Hz), 1.56-1.62 (4H, m),1.73-2.20 (4H, m), 3.80 (1H, d, J=6.2 Hz), 4.20 (2H, q, J=7.1 Hz), 5.39(1H, d, J=6.2 Hz), 7.20-7.40 (4H, m).

IR (neat) ν cm⁻¹: 3485, 2958, 1714.

[α]_(D) ²⁵=−41.9° (c=1.0, chloroform).

(2) Production of [1-(hydroxymethyl)cyclopentyl](2-chlorophenyl)methanol

Lithium aluminum hydride (0.64 g, 16.8 mmol) was mixed with ether (20ml) and cooled to −10° C. Thereto was added dropwise a solution of ethyl1-(1-hydroxy(2-chlorophenyl)methyl)cyclopentanecarboxylate (3.1 g, 11.2mmol) in ether (5 ml) at the same temperature over 15 min, and themixture was stirred at −10° C. for 1 h, and at room temperature for 3 h.The mixture was cooled to −20° C. and 10%—NaHCO₃ aq. (2 ml) was addeddropwise, then 20%—NaOH aq. (2 ml) was added dropwise. The mixture wasstirred for 30 min and sludge was removed by decantation. The organiclayer was washed with water (50 ml), dried over anhydrous sodiumsulfate, concentrated to dryness, and purified by silica gel columnchromatography (hexane:ethyl acetate =2:1) to give the title compound2.2 g (quant.) as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.10-1.17 (1H, m), 1.52-1.77 (7H, m), 2.80(2H, br), 3.48 (1H, d, J=11.0 Hz), 3.76 (1H, d, J=11.0 Hz), 5.35 (1H,s), 7.22-7.35 (3H, m), 7.69 (1H, dd, J=1.7 and 4.7 Hz).

IR (neat) ν cm⁻¹: 3349, 2955, 2871, 1707.

(3) Production of8-chloro-6-(2-chlorophenyl)-7,9-dioxa-8-phosphospiro[4.5]decan-1-one

[1-(Hydroxymethyl)cyclopentyl](2-chlorophenyl)methanol (2.1 g, 8.72mmol) was diluted with dichloromethane (15 ml), and under reflux, asolution of phosphorus oxychloride (1.4 g, 8.73 mmol) in dichloromethane(10 ml) was added dropwise over 30 min. The mixture was stirred at reflux temperature for 5 h and concentrated to give crude title compound asa colorless oil.

(4) Production of6-(2-chlorophenyl)-8-hydroxy-7,9-dioxa-8-phosphospiro[4.5]decan-8-one

Sodium hydroxide (1.1 g) was dissolved in water (10 ml) and heated to 95to 100° C. A solution (3 ml) of8-chloro-6-(2-chlorophenyl)-7,9-dioxa-8-phosphospiro[4.5]decan-8-one(8.72 mmol) in diethyl ether was added over 15 min. The mixture wasstirred at the same temperature for 20 min, and after allowing thereaction mixture to cool to 60° C., concentrated hydrochloric acid (3ml) was added. The mixture was cooled to 13-15° C. and the precipitatedwhite crystals were collected by filtration, washed successively withwater (5 ml) and ether (5 ml) and dried in vacuo to give the titlecompound (2.1 g, 79.5%) as white crystals. The enantiomer excess of theobtained white crystals was measured by high performance liquidchromatography (Condition E) and found to be 92%.

This was recrystallized from ethanol and purified to give the titlecompound (1.3 g, 49.7%, 99% ee) as white crystals (m.p. 205-206° C.(dec.)).

¹H-NMR (400 MHz, CDCl₃) δ: 1.25-1.34 (4H, m), 1.45-1.52 (2H, m),1.88-1.92 (2H, m), 4.02 (1H, dd, J=11.2 and 24.8 Hz), 4.37 (1H, d,J=11.2 Hz), 6.03 (1H, d, J=1.7 Hz), 7.24-7.35 (3H, m), 7.59 (1H, dd,J=7.5 and 1.8 Hz).

[α]_(D) ²⁰=−52.0° (c=0.5, ethanol).

EXAMPLE 28 (1) Production of ethyl1-[(2,4-dichlorophenyl)(hydroxy)methyl]cyclopentanecarboxylate

(S)-tBuBisP*-RuBr₂ (16 mg) was placed in a reactor and deaerated. Aftersubstitution with argon, a mixture of ethyl1-(2,4-dichlorobenzoyl)cyclopentanecarboxylate (2.8 g, 5.6 mmol) andmethanol-water (101) (30 ml) was added. Under 70° C. and hydrogenpressure (6 kg/cm²), the mixture was stirred for 30 h and concentrated.This was diluted with ethyl acetate (50 ml), washed with water andconcentrated to dryness. This was purified by silica gel columnchromatography (hexane:ethyl acetate=4:1) to give the title compound(0.91 g, 41.3%) as a colorless oil. The enantiomer excess of thisproduct was measured by high performance liquid chromatography(Condition F) and found to be 92%.

¹H-NMR (400 MHz, CDCl₃) δ: 1.25 (3H, t, J=7.1 Hz), 1.56-2.18 (8H, m),3.83 (1H, d, J=6.3 Hz), 4.19 (2H, m), 5.33 (1H, d, J=6.3 Hz), 7.22-7.42(3H, m).

IR (neat) ν cm⁻¹: 3476, 2959, 1720.

[α]_(D) ²⁴=−34.7° (c=1.0, chloroform).

(2) Production of(2,6-dichlorophenylmethyl)[1-(hydroxymethyl)cyclopentyl]methanol

Lithium aluminum hydride (0.29 g, 7.6 mmol) was suspended in ether (10ml) and the suspension was cooled to −5° C. to 0° C. Thereto was addeddropwise a solution of ethyl1-[(2,4-dichlorophenyl)(hydroxy)methyl]cyclopentanecarboxylate (1.6 g, 5mmol) in ether (5 ml) while maintaining at not higher than 10° C. over30 min. The mixture was stirred at the same temperature for 1 h and atroom temperature for 3 h, cooled to 0° C., and 10%—NaHCO₃ aqueoussolution (2 ml) and 20%—NaOH aqueous solution (2 ml) were addeddropwise. The mixture was stirred for 30 min, and an insoluble materialwas removed by decantation. This was extracted twice with ethyl acetate(100 ml). The organic layer was combined, and the mixture was washedwith water, dried over anhydrous sodium sulfate and concentrated todryness to give the title compound (1.3 g, 95.5%) as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.53-1.72 (8H, m), 2.80 (1H, brs), 3.50 (1H,dd, J=4.0 Hz and 10.7 Hz), 3.62 (1H, d, J=3.4 Hz), 3.72 (1H, dd, J=3.4Hz and 10.7 Hz), 5.29 (1H, d, J=4.1 Hz), 7.26-7.36 (2H, m), 7.63 (1H, d,J=8.5 Hz).

(3) Production of8-chloro-6-(2,4-dichlorophenyl)-7,9-dioxa-8-phosphospiro[4.5]decan-8-one

(2,6-Dichlorophenylmethyl)[1-(hydroxymethyl)cyclopentyl]methanol (1.3 g,4.72 mmol) was diluted with dichloromethane (8 ml), and under reflux, asolution of phosphorus oxychloride (0.72 g, 4.72 mmol) indichloromethane (5 ml) was added dropwise over 30 min. The mixture wasstirred at reflux temperature for 5 h and concentrated to give a crudetitle compound as a colorless oil.

(4) Production of6-(2,4-dichlorophenyl)-8-hydroxy-7,9-dioxa-8-phosphospiro[4.5]decan-8-one

Sodium hydroxide (0.57 g) was dissolved in water (6 ml) and the mixturewas heated to 95 to 100° C. A solution (2 ml) of8-chloro-6-(2,4-dichlorophenyl)-7,9-dioxa-8-phosphospiro[4.5]decan-8-one(4.42 mmol) in diethyl ether was added over 15 min and the mixture wasstirred at the same temperature for 20 min. The reaction mixture wasallowed to cool to 60° C. and concentrated hydrochloric acid (3 ml) wasadded. The mixture was cooled to 13 to 15° C. and the precipitated whitecrystals were collected by filtration, washed successively with water (2ml) and ether (2 ml), and dried in vacuo to give the title compound(0.81 g, 50.7%) as white crystals. The crystals were recrystallized forpurification from ethanol to give the title compound as white crystals(500 mg, 37%, m.p. 208-209° C.). The enantiomer excess of this productwas measured by high performance liquid chromatography (Condition E) andfound to be 99.5%.

¹H-NMR (400 MHz, CDCl₃) δ: 1.28-1.93 (5H, m), 4.01 (1H, dd, J=11.2 and24.7 Hz), 4.35 (1H, d, J=11.2 Hz), 5.96 (1H, s), 7.26-7.40 (3H, m).

[α]²⁷ _(D)=−49.2° (c=0.5, MeOH).

EXAMPLE 29 (1) Production of ethyl1-[hydroxy(phenyl)methyl]cyclopropanecarboxylate

(S)-^(t)BuBisP*-RuBr₂ (25 mg) was placed in a reaction vessel anddeaerated. After substitution with argon, a mixture of ethyl1-benzoylcyclopropanecarboxylate (3.3 g, 1.0 mmol) and methanol-water(10/1) (33 ml) was added. The mixture was stirred at 70° C. and hydrogenpressure (6 kg/cm²) for 24 h, after which the reaction mixture wasconcentrated. This was concentrated to dryness, diluted with ethylacetate, washed with water and purified by silica gel columnchromatography (hexane:ethyl acetate=4:1) to give the title compound(1.53 g, 46.3%) as a colorless oil. The enantiomer excess of thisproduct was measured by high performance liquid chromatography(Condition F) and found to be 85%.

¹H-NMR (400 MHz, CDCl₃) δ: 0.80-0.84 (1H, m), 0.94-0.99 (1H, m), 1.17(3H, t, J=7.1 Hz), 1.17-1.38 (2H, m), 3.47 (1H, d, J=6.7 Hz), 4.11 (2H,q, J=7.1 Hz), 4.85 (1H, d, J=6.7 Hz), 7.26-7.41 (5H, m).

(2) Production of [1-(hydroxymethyl)cyclopropyl](phenyl)methanol

Lithium aluminum hydride (0.39 g, 10.2 mmol) was mixed with ether (12ml) and the mixture was cooled to −10° C. Thereto was added dropwise asolution of ethyl 1-[hydroxy(phenyl)methyl]cyclopropanecarboxylate (1.5g, 6.8 mmol) in ether (3 ml) at the same temperature over 15 min, andthe mixture was stirred at −10° C. for 1 h and at room temperature for 2h. Thereafter, the mixture was cooled to −20° C., and 10% NaHCO₃ aq. (2ml) was added dropwise. Then, 20% NaOH aq. (2 ml) was added dropwise,and the mixture was stirred for 30 min. Sludge was removed bydecantation and the organic layer was washed with water (50 ml), driedover anhydrous sodium sulfate, concentrated to dryness, and purified bysilica gel column chromatography (hexane:ethyl acetate=3:1) to give thetitle compound (1.2 g, 98.9%) as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 0.40-0.73 (4H, m), 2.70 (2H, brs), 3.20 (1H,d, J=11.3 Hz), 3.76 (1H, d, J=11.3 Hz), 4.82 (1H, s), 7.26-7.41 (5H, m).

[α]_(D) ²⁴=17.2° (c 0.5, chloroform).

(3) Production of6-chloro-4-phenyl-5,7-dioxa-6-phosphospiro[2.5]octane-6-one

[1-(Hydroxymethyl)cyclopropyl](phenyl)methanol (1.0 g, 5.61 mmol) wasdiluted with dichloromethane (9 ml), and triethylamine (1.6 g, 15.8mmol) was added. The mixture was cooled to 0 to 5° C., and a solution ofphosphorus oxychloride (0.87 g, 5.61 mmol) in dichloromethane (3 ml) wasadded dropwise over 15 min at the same temperature. After the dropwiseaddition, the mixture was stirred for 2 h. Then, water (5 ml) was addeddropwise and the mixture was partitioned. The organic layer was driedover anhydrous magnesium sulfate and concentrated. Dry ether (5 ml) wasadded to give a suspension and the suspension was filtrated to give thetitle compound (510 mg) as pale-red crystals. In the same manner asabove, the title compound was obtained from the mother liquor aspale-red crystals (100 mg), (total yield: 42.0%).

¹H-NMR (400 MHz, CDCl₃) δ: 0.34-0.40 (1H, m), 0.53-0.59 (1H, m),0.67-0.71 (2H, m), 3.72 (1H, dd, J=11.7and 29.3 Hz), 4.96 (1H, dt, J=2.1and 11.7 Hz), 5.89 (1H, d, J=2.2 Hz), 7.27-7.29 (2H, m), 7.36-7.40 (3H,m).

(4) Production of6-hydroxy-4-phenyl-5,7-dioxa-6-phosphospiro[2.5]octane-6-one

Sodium hydroxide (320 mg) was dissolved in water (3.2 ml) and themixture was heated to 95-100° C.6-Chloro-4-phenyl-5,7-dioxa-6-phosphospiro[2.5]octane-6-one (600 mg,2.64 mmol) was added over 15 min, and the mixture was stirred at thesame temperature for 10 min. The mixture was allowed to cool to 60° C.and concentrated hydrochloric acid (1 ml) was added. The mixture wascooled to 13 to 15° C. and ether (1 ml) was added. The mixture wasstirred and the precipitated white crystals were collected byfiltration, washed successively with water (2 ml) and ether (2 ml) anddried in vacuo. The obtained pale-brown crystals were recrystallizedfrom ethanol for purification to give the title compound (380 mg, 83%)as white crystals. The enantiomer excess of this product was measured byhigh performance liquid chromatography (Condition E) and found to be notless than 97%.

¹H-NMR (400 MHz, CDCl₃) δ: 0.23-0.27 (1H, m), 0.43-0.48 (1H, m),0.54-0.58 (2H, m), 3.50 (1H, dd, J=11.3 Hz, 22.7 Hz), 4.81 (1H, d,J=11.2 Hz), 5.77 (1H, s), 7.30-7.52 (5H, m).

[α]_(D) ²⁴=−46.1° (c=0.5, methanol).

COMPARATIVE EXAMPLE 1 Production of salt of1-(6,7-dimethoxynaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanoland (1S,2R)-cis-2-benzamidecyclohexanecarboxylic acid

A racemate (50 mg) of1-(6,7-dimethoxynaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanoland (1S,2R)-cis-2-benzamidecyclohexanecarboxylic acid (37.9 mg) weredissolved in isopropyl alcohol (0.6 ml). The solution was stood stillovernight in a refrigerator, and the precipitate was collected byfiltration to give crystals (8.4 mg, yield 19%). As a result of the HPLCanalysis (Condition B), the diastereomer excess was found to be 3% de.

COMPARATIVE EXAMPLE 2 Production of salt of1-(6,7-dimethoxynaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanoland (S)-1-phenylethylsulfamic acid

A racemate (25 mg) of1-(6,7-dimethoxynaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanoland (S)-1-phenylethylsulfamic acid (15.4 mg) were dissolved in ethanol(0.5 ml). The solution was stood still overnight in a refrigerator, andthe precipitate was collected by filtration to give crystals (10 mg,yield 50%). As a result of the HPLC analysis (Condition B), thediastereomer excess was found to be 2% de.

COMPARATIVE EXAMPLE 3 Production of salt of1-(6,7-dimethoxynaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanoland (S)-mandelic acid

A racemate (50 mg) of1-(6,7-dimethoxynaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanoland (S)-(+)-mandelic acid (23.3 mg) were dissolved in ethanol (1.0 ml).The solution was stood still overnight in a refrigerator but precipitatewas not observed.

INDUSTRIAL APPLICABILITY

According to the production method of an optically active form ofcompound (I) of the present invention, a novel diastereomer salt of anoptically active naphthalene derivative, useful as a pharmaceuticalagent, can be obtained extremely easily. By separation and subsequentdecomposition of the diastereomer salt, an optically active naphthalenederivative having a high optical purity can be obtained efficiently.Since a reagent for optical resolution can be recovered and reused, themethod is superior as an industrial production method. The opticallyactive compound (IIa) of the present invention can be utilized as areagent for resolution of a racemate of an optically active amine, oroptically active intermediates, such as pharmaceutical agents,agricultural chemicals, liquid crystals and the like. According to theproduction method of the optically active compound (IIa) of the presentinvention, an optically pure and optically active form can be producedefficiently in a high yield by a convenient method.

What is claimed is:
 1. A compound represented by the formula (IIa):

wherein ring A is a benzene ring optionally having 1 to 5 substituentsselected from the group consisting of (1) C₁₋₆ alkyl group which mayhave a substituent selected from the group consisting of (i) halogenatom, (ii) C₁₋₇ alkoxy group, (iii) C₁₋₇ alkylthio group, (iv) hydroxygroup, (v) acetylamino, (vi) benzoylamino, (vii) methanesulfonylaminoand (viii) benzenesulfonylamino, (2) hydroxy group, (3) linear orbranched C₁₋₆ alkoxy group, (4) C₁₋₄ alkanoyloxy group, (5) carbamoyloxygroup which may have 1 or 2 C₁₋₄ alkyl groups, (6) thiol group, (7) C₁₋₄alkyithio group, (8) C₁₋₄ alkanoylthio group, (9) nitro group, (10) C₁₋₆alkanoyl group, (11) C₁₋₄ alkylsulfonyl group, (12) benzenesulfonyl,(13) p-toluenesulfonyl, (14) carbamoyl group, (15) mono- or di-C₁₋₁₀alkylcarbamoyl group, (16) mono- or di-C₆₋₁₄ arylcarbamoyl group, (17)mono- or di-C₇₋₁₆ aralkylcarbamoyl group, (18) sulfamoyl group, (19)mono- or di-C₁₋₁₀ alkylsulfamoyl group, (20) mono- or di-C₆₋₁₄arylsulfamoyl group, (21) mono- or di-C₇₋₁₆ aralkylsulfamoyl group, (22)C₁₋₄ alkoxy-carbonyl group, (23) halogen atom and (24) methylenedioxygroup which may have a substituent selected from the group consisting of(i) halogen, (ii) nitro group, (iii) hydroxy group and (iv) amino group;Alk is a C₂₋₄ alkylene optionally having substituents selected from thegroup consisting of (1) C₁₋₄ alkyl group, (2) C₁₋₄ alkoxy group, (3)hydroxy group, (4) amino group, (5) nitro group and (6) halogen group;and * shows the position of an asymmetric carbon, or a salt thereof. 2.The compound of claim 1, which is an optically active form.